Peptide combinations and uses thereof in treating dust mite allergy

ABSTRACT

The invention relates to combinations of peptides or variants thereof derived from a portion of an amino sequence of CM a house dust mite allergen, e.g. the allergens Der p 1, Der f 1, Der p 2 and/or Der f 2. Such peptides comprise at least one T cell epitope and a significant high number of patients in a worldwide population will have HLA alleles with the potential to bind the peptides of the peptide combinations. The invention also relates to the use of such peptide combinations in relieving an immune response caused by a dust mite.

FIELD OF THE INVENTION

The present invention relates to compositions of peptides derived from ahouse dust mite allergen and methods of using such compositionsmodulating an immune response, for treating a subject for an allergicresponse and/or for inducing or promoting immunological tolerance in asubject, and in diagnostic methods and kits.

BACKGROUND

Allergy to dust mites affects populations in most parts of the world.The most common dust mites are the European house dust mite(Dermatophagoides pteronyssinus) and the American house dust mite(Dermatophagoides farinae), which contain the major allergens Der p1/Der p 2 and Der f 1/Der f 2, respectively. Other common dust mites arefound in subtropical/tropical regions around the world, for exampleBlomia tropicalis containing the major allergens Blo t 1 and Blo t 2 andEuroglyphus maynei containing the major allergens Eur m 1 and Eur m 2.

Today, the treatment of dust mite allergy is performed withallergen-specific immunotherapy products based on whole, intact ormodified allergens typically administered as a complex extract made fromdust mites. Typically, such products are administered by subcutaneousinjection or by the sublingual route to a subject over an extendedperiod of time, frequently months or years and are now appreciated toinduce a state of “tolerance” in the subject. The mechanism of action isthought to involve induction of IgG inhibitory antibodies, suppressionof mast cell/basophil reactivity, suppression of T-cell responses, thepromotion of T-cell anergy, and/or clonal deletion, and in the longterm, decrease in the levels of allergen specific IgE.

Unfortunately, allergen-specific immunotherapy bears the risk ofIgE-mediated adverse events including serious anaphylactic responses.Therefore, this therapy is not as widely offered to allergic subjects asits beneficial effect actually justifies. In the recent years, it hasbeen suggested to treat allergy using smaller fragments (peptides) ofthe primary amino acid sequence of allergens (e.g. of the majorallergens), that contain one or more epitope(s) recognized by T cellsregulating the allergic reaction. This concept has been termed peptideimmunotherapy (PIT), in which, repeated doses of the peptide isadministered, typically by intradermal injection, to a subject (Moldaverand Larche 2011).

More specifically on the molecular level, peptides are bound by HumanLeucocyte Antigen (HLA) class II on the surface of Antigen PresentingCells (APC). This peptide-HLA complex is then recognized by specificT-cell receptors on the cell surface of T-cells that upon interactionwith the APCs becomes activated. A major difference of peptide-basedimmunotherapy and therapies based on full-length allergens is that thisinteraction is thought to occur without a concomitant antibody mediated“danger signal” being elicited.

This is thought to drive the T-cell response in a more tolerogenicdirection.

Peptide-based immunotherapy (PIT) represents a potentially attractivealternative to allergen extracts, with a more favorablesafety/tolerability profile and a significantly shorter treatmentregimen than existing therapies. In contrast to therapies based onintact allergens, PIT solely addresses the T-cell compartment of theimmune system without engaging existing antibody responses because ofthe lack of antibody epitopes due to the smaller size of peptidescompared to allergens. Consequently, no IgE-mediated adverse events areexpected although they are often seen when treating allergy withtraditional allergen-based immunotherapy products. Peptide immunotherapyis today in clinical development and does seem to have a favorablesafety profile over the whole-allergen based vaccines.

A shortcoming of using the T cell epitope-containing peptides is,however, associated with the restriction of each peptide to only bind asubset of the naturally occurring HLA Class II molecules within thehuman population. A mix of several peptides covering different HLA ClassII alleles is therefore mandatory to generate a broadly actingimmunotherapy allergy treatment. As this repertoire of HLA Class IIalleles varies from one person to another and from one ethnic populationto another, it is challenging to provide peptide-based immunotherapiesthat can be offered to allergic subjects of any geographic region in theworld unless numerous peptides are included in the vaccine. Taken intoconsideration the enormous costs and risks in the clinical developmentof new vaccines and the increasing demands from regulatory bodies tomeet high standards for toxicity testing, dose justification, safety andefficacy trials, it is desirable to provide peptide vaccines containingas few peptides as possible, but at the same time to be able to treatthe majority of dust mite allergic subjects in a worldwide populationwith the same immunotherapy product.

Such a product should comprise a combination of peptides that incombination are able to bind the worldwide HLA Class II allelerepertoire, and the resulting peptide-HLA complexes should be recognizedas T cell epitopes in the subject so as to induce tolerogenicimmunological reactions. Recent studies in mice have indicated thatpeptide immunotherapy using one peptide alone did not reduce theseverity of allergic airway inflammation, but that it is at leastrequired that the mice are treated with two peptides that match the MHCmolecules of the mice being treated (Mackenzie K J et al 2013).

International patent applications WO93/08280, WO94/24281, WO95/28424,WO2009/022156, WO95/28424 and WO2010/018384, respectively, and USapplication US20130302338 relate to peptides of house dust miteallergens and their use in treating house dust mite allergy.

SUMMARY

The present inventors have found it possible to assemble peptidecombinations consisting of few peptides, such as three, four, five orsix peptides, which have HLA Class II allele repertoire covering asignificantly high fraction of a worldwide population and which alsoproduce a T cell response in a significantly high fraction of a donorpopulation allergic to a house dust mite.

The invention provides a number of compositions comprising peptidecombinations having high worldwide HLA Class II allele coverage. Asdisclosed herein, such peptide combinations may be assembled by firstproviding a set of T cell epitope containing peptides (for example asdisclosed in Example 3), then estimating the HLA Class II allelecoverage of individual T cell epitope containing-peptides (for exampleas disclosed in Examples 10), then combining peptides with different HLAalleles to cover the HLA Class II allele repertoire of a worldwidepopulation (for example as disclosed in Example 6) and then verifying ina qualified donor population (for example as disclosed in Example 2)that the suggested peptide combinations are able to produce a T cellresponse in a high fraction of the population (For example as describedin Example 7).

Thus, there is herein provided a combination of peptides (in thefollowing also named “peptide combination” or “peptide mix”) for use asan “allergy vaccine” in the treatment of allergy to a house dust miteallergen, which is eligible for the majority of the world population.The peptides selected for the herein disclosed peptide combinationsderive from one or more of the house dust mite allergens Der p 1, Der p2, Der f 1 and Der f 2, and optionally Der p 4, and are shown to producea T cell response in many donors and to have a satisfactorily highworldwide HLA Class II coverage. It should be understood that peptidesof a peptide combination as disclosed herein primarily are distinctpeptides derived from different regions of the house dust miteallergens, optionally wherein the amino acid residues of one distinctpeptide overlap with few amino acid residues of another distinct peptidesuch as overlapping with less than 13, such as less than 12, 11, 10 or 9amino acid residues. Tables 9 and 10 report peptides shown to produce aT cell response in a high fraction of the donor population (“highresponder peptides”-derived from FIGS. 1 to 8) and wherein peptides arecollected in groups of distinct peptides. Therefore, the inventionrelates in a first aspect to a composition comprising at least threepeptides, wherein the composition comprises peptides selected from atleast three of the following peptide groups:

-   group 26.: a parent peptide with the amino acid sequence SEQ ID NOs:    82 (pep-110), 269 (pep-125), 70 (pep-099) or 253 (pep-012); or a    variant thereof (e.g. SEQ ID NOs: 223, 247, 224, 248);-   group 24.: a parent peptide with the amino acid sequence SEQ ID NOs:    271 (pep-131), 67 (pep-096), 79 (pep-108), 256 (pep-031) or 270    (pep-126); or a variant thereof (e.g. SEQ ID NOs: 279, 241);-   group 14.: a parent peptide with the amino acid sequence SEQ ID NOs:    268 (pep-130) or 22 (pep-054); or a variant thereof;-   group 1.: a parent peptide with the amino acid sequence SEQ ID NO:    90 or a variant thereof;-   group 2.: a parent peptide with the amino acid sequence SEQ ID NO:    280 or a variant thereof (e.g. SEQ ID NO: 98);-   group 3.: a parent peptide with the amino acid sequence SEQ ID NO: 9    (pep-041) or a variant thereof (e.g. SEQ ID NO: 99);-   group 4.: a parent peptide with the amino acid sequence SEQ ID NO:    10 (pep-042) or a variant thereof (e.g. SEQ ID Nos: 259, 102, 161,    281, 282);-   group 5.: a parent peptide with the amino acid sequence SEQ ID NO:    11 (pep-043) or a variant thereof (e.g. SEQ ID NO: 103, 281, 282);-   group 6.: a parent peptide with the amino acid sequence SEQ ID NO:    12 (pep-044) or a variant thereof (e.g. SEQ ID NOs: 105, 283, 106);-   group 7.: a parent peptide with the amino acid sequence SEQ ID NOs:    42 (pep-072) or 249 (pep-022); or a variant thereof (e.g. SEQ ID    NOs: 166);-   group 8.: a parent peptide with the amino acid sequence SEQ ID NO:    15 (pep-047) or a variant thereof (e.g. SEQ ID NOs: 111, 270, 112);-   group 9.: a parent peptide with the amino acid sequence SEQ ID NOs:    266 (pep-123), 255 (pep-025), 46 (pep-075) or 17 (pep-049); or a    variant thereof (e.g. SEQ ID NOs: 271, 114, 173, 115, 174);-   group 10.: a parent peptide with the amino acid sequence SEQ ID NOs:    18 (pep-050), 258 (pep-122) or 267 (pep-124); or a variant thereof    (e.g. SEQ ID NOs: 117, 176);-   group 11.: a parent peptide with the amino acid sequence SEQ ID NO:    120; or a variant thereof;-   group 12.: a parent peptide with the amino acid sequence SEQ ID NOs:    20 (pep-052) or 49 (pep-078); or a variant thereof (e.g. SEQ ID NOs:    121, 180);-   group 13.: a parent peptide with the amino acid sequence SEQ ID NO:    21 (pep-053) or a variant thereof;-   group 15.: a parent peptide with the amino acid sequence SEQ ID NOs:    52 (pep-081) or 23 (pep-055, 272); or a variant thereof (e.g. SEQ ID    Nos: 273, 128, 187, 129, 188);-   group 16.: a parent peptide with the amino acid sequence SEQ ID NO:    26 (pep-058) or a variant thereof (e.g. SEQ ID NOs: 133, 192, 274,    191);-   group 17.: a parent peptide with the amino acid sequence SEQ ID NOs:    29 (pep-061), 58 (pep-087), 251 (pep-10) or 252 (pep-011); or a    variant thereof (e.g. SEQ ID NOs: 140, 199);-   group 18.: a parent peptide with the amino acid sequence SEQ ID NO:    71 (pep-100) or a variant thereof;-   group 19.: a parent peptide with the amino acid sequence SEQ ID NO:    72 (pep-101) or a variant thereof (e.g. SEQ ID NOs: 60 (pep-089),    227);-   group 20.: a parent peptide with the amino acid sequence SEQ ID NOs:    61 (pep-090), 73 (pep-102) or 276; or a variant thereof (e.g. SEQ ID    NOs: 277, 205, 229, 206, 230);-   group 21.: a parent peptide with the amino acid sequence SEQ ID NO:    62 (pep-091) or a variant thereof (e.g. SEQ ID NO: 208);-   group 22.: a parent peptide with the amino acid sequence SEQ ID NOs:    63 (pep-092) or 278; or a variant thereof (e.g. SEQ ID NO: 222,    210);-   group 23.: a parent peptide with the amino acid sequence SEQ ID NO:    77 (pep-106) or a variant thereof (e.g. SEQ ID NO: 238); and group    25.: a parent peptide with the amino acid sequence SEQ ID NO: 81    (pep-109) or a variant thereof (e.g. SEQ ID NOs: 221, 245, 246).

The invention provides in a second aspect a pharmaceutical compositioncomprising a composition as defined herein.

The invention provides in a third aspect to a method for relieving orreducing (e.g. treating) an immune response triggered by an allergen ofa dust mite (e.g. house dust mite) in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a composition described herein.

The invention provides in a further aspect, a method for relieving oneor more symptoms of an immune response triggered by an allergen of adust mite in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a composition describedherein.

The invention provides in a further aspect, a method for inducingimmunological tolerance against an allergen of a dust mite, comprisingadministering to the subject a therapeutically effective amount of acomposition described herein.

In further aspects, the invention relates to a composition as definedherein for use in a method defined herein, e.g. a composition as definedherein for use in relieving an immune response triggered by an allergenof a dust mite in a subject in need thereof; for use in relieving one ormore symptoms of an immune response triggered by an allergen of a dustmite in a subject in need thereof; and/or for inducing immunologicaltolerance against an allergen of a dust mite in a subject in needthereof.

In further aspects, the invention relates to the use of a composition asdefined herein for the preparation of a medicament for use in a methoddefined herein, e.g. the use of a composition as defined herein for thepreparation of a medicament for use in relieving an immune responsetriggered by an allergen of a dust mite in a subject in need thereof;for use in relieving one or more symptoms of an immune responsetriggered by an allergen of a dust mite in a subject in need thereof;and/or for inducing immunological tolerance against an allergen of adust mite in a subject in need thereof.

In still further aspects, the invention relates to a kit comprising acompartment and instructions, wherein the compartment comprises acomposition described herein and wherein the instructions are for use intreating allergy to dust mites, such as house dust mites.

In still further aspects, the invention relates to a method ofdetermining whether T cells of a subject in need of treatment recognizea composition as defined herein, comprising contacting T cells obtainedfrom the subject with said composition or a single peptide thereof anddetecting whether the T cells are stimulated by said composition orsingle peptide.

In still another aspect, the invention relates to a diagnostic kitcomprising a composition defined herein.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: This figure shows T-cell recognition of overlapping 20mersderived from Der p 1. FIG. 1 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Table 2).

FIG. 2: This figure shows T-cell recognition of overlapping 20mersderived from Der f 1. FIG. 2 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Table 2).

FIG. 3: This figure shows T-cell recognition of overlapping 20mersderived from Der p 2. FIG. 3 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Table 3).

FIG. 4: This figure shows T-cell recognition of overlapping 20mersderived from Der f 2. FIG. 4 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Table 3).

FIG. 5: This figure shows T-cell recognition of overlapping 15mersderived from Der p 1. FIG. 5 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Tables 4 and 6).

FIG. 6: This figure shows T-cell recognition of overlapping 15mersderived from Der f 1. FIG. 6 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Tables 4 and 6).

FIG. 7: This figure shows T-cell recognition of overlapping 15mersderived from Der p 2. FIG. 7 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Tables 5 and 6).

FIG. 8: This figure shows T-cell recognition of overlapping 15mersderived from Der f 2. FIG. 8 shows the fraction of donors (y-axis=%responders) responding to a given peptide (x-axis shows peptide IDnumbers found in Tables 5 and 6).

FIG. 9a : This figure shows the fraction of donors (% responders)responding to a peptide combination (shown in Table 14) in an in vitro Tcell proliferation assay as described in Example 3.

FIGS. 9b and 9c : The figures show the fraction of donors (% responders)responding to peptide combination 17f in comparison to peptidecombination 17 in a T cell assay as described in Example 3. The T cellresponses of individual peptides are also shown and their calculatedcumulated responses add up to the responses measured for the peptidecombination.

FIG. 9d : This figure shows the calculated percentage respondersresponding in an T cell assay to peptide combinations numbers 17f, 17l,17p, 17q, 17s, 17t, 17u and 17v, respectively.

FIG. 9e : This figure shows % responders (as measured) in a T cell assayto a subset of individual peptides (pep-058, pep-075, pep-091, pep-110,pep-123, pep-130 and pep-131) using a subset of 31 donors having aworldwide HLA Class II coverage of about 88%.

FIG. 9f : This figure shows % responders in a T cell assay to peptidecombinations 17p, 17s, 17f, and 8, respectively, and a peptidecombination consisting of only peptides pep-110, pep-130 and pep-131.

FIG. 9g : This figure shows % responders (as calculated based onindividual peptides) to peptide combinations 17p, 17s, 17f, 3-pep-mix of110+130+131 and 2-pep-mix of 110 and 131.

FIG. 9h : This Figure shows the average number of peptides in peptidecombinations 17p, 17s, 17f, 3-pep-mix 110+130-131 and the 2-pep-mix110+131 that a donor of the test population is able to respond to.

FIG. 9i : This figure shows % responders of individual peptides 058,075, 110, 123, 130, 131 and the peptides of peptide combination 8(HDM03W, HDM101A, HDM203B, HDM205, HDM26B and HDM35A) when tested in a Tcell assay using a subset of the original donor population.

FIG. 9j : This figure shows the % responders in a T cell assay topeptide combinations 17f and 8.

FIG. 9k : This figure shows % responders (as calculated based on %responders to individual peptides to peptide combinations 17p, 17s, 17f,8, the three combination (110+130+131) and the two peptide combination(110+131) based on T cell assay with a subset of 22 donors having about78% worldwide HLA Class II coverage.

FIG. 9l : This figure shows % responders shown to respond to peptidecombinations 17p, 17s, 17f, and 8 and a peptide combination consistingof only peptides pep-110, pep-130 and pep-131, when analyzed in a T cellassay using a subset of 31 donors having about 88% worldwide HLA ClassII coverage.

FIGS. 10 to 19: These figures refer to the estimation of valency ofvarious peptide combinations according to the description of valencydisclosed in Example 10. The figures show the fraction of a virtualpopulation of patients (Y-axis=% patients) that have HLA Class IIalleles potentially able to bind (i.e. able to respond to) 0, 1, 2, 3, 4and 5 peptides, respectively, in the combination (Data indicated withbars). Valency data are shown both with respect to peptides only derivedfrom the HDM group 1 allergens Der p 1 or Der f 1 (indicated at thex-axis as Grp 1); peptides only derived from the HDM group 2 allergensDer p 2 or Der f 2 (indicated at the x-axis as Grp 2); peptides derivedonly from Der p (i.e. allergens Der p 1 or Der p 2 (indicated at thex-axis as Der p) and peptides derived only from Der f (i.e. allergensDer f 1 or Der f 2 (indicated at the x-axis as Der f). Finally, valencyis also estimated with respect to all peptides in the combination(indicated at the X-axis as “all”). The Figures also shows the predictedfraction of patients (% patients) that will have HLA alleles potentiallyable to bind a given number of peptides or more in the peptidecombination (data points shown as X)

FIG. 10a shows valency for peptide combination 5, wherein the estimationis based on predicted HLA allele coverage of alleles shown in Table 8.

FIG. 10b shows valency for peptide combination 5, wherein the estimationis based on measured HLA allele coverage of alleles shown in Table 8.

FIG. 11a shows valency for peptide combination 17f, wherein theestimation is based on predicted HLA allele coverage of alleles shown inTable 8.

FIG. 11b shows valency for peptide combination 17f, wherein theestimation is based on measured HLA allele coverage of alleles shown inTable 8.

FIG. 12a shows valency for peptide combination 8, wherein the estimationis based on predicted HLA allele coverage of alleles shown in Table 8.

FIG. 12b shows valency for peptide combination 8, wherein the estimationis based on measured HLA allele coverage of alleles shown in Table 8.

FIG. 13 shows valency for peptide combination 9, wherein the estimationis based on predicted HLA allele coverage of alleles shown in Table 17.

FIG. 14 shows valency for peptide combination 17d, wherein theestimation is based on predicted HLA allele coverage of alleles shown inTable 17.

FIG. 15 shows valency for peptide combination 17f, wherein theestimation is based on predicted HLA allele coverage of alleles shown inTable 17.

FIG. 16 shows valency for peptide combination 17p, wherein theestimation is based on predicted HLA allele coverage of alleles shown inTable 17.

FIG. 17 shows valency for peptide combination 17s, wherein theestimation is based on predicted HLA allele coverage of alleles shown inTable 17.

FIG. 18 shows valency for peptide combination 17x, wherein theestimation is based on predicted HLA allele coverage of alleles shown inTable 17.

FIG. 19 shows valency for peptide combination 23, wherein the estimationis based on predicted HLA allele coverage of alleles shown in Table 17.

FIG. 20 shows the predicted average number of peptides that a patient ofthe virtual patient population described in Example 10 potentially canrespond to in the peptide combinations shown (i.e. have HLA Class IIalleles potentially able to bind to peptides in the combination, whereinthe estimation is based on predicted HLA allele coverage of allelesshown in Table 17. FIG. 20 shows that the patient population in averagemay be able to respond to 1.8 peptides of the peptide combination named“core 2” (peptides pep-110+pep-131). The patient population may inaverage be able to respond to 2.8 peptides of the peptide combinationnamed Core 3 (peptides pep-110, pep-131 and pep-130), whereas thepatient population may respond to 2.4 peptides of the three-peptidecombination named Core 3_53 (peptides pep-110, pep-131 and pep-053). Thepeptides of Core 3 are present in the peptide combinations numbered 17f,17p and 17s (contain 5 peptides), all comprising a high average numberof peptides (3.5, 4.6, and 3.8, respectively) that the patientpopulation can respond to. For comparison purposes, the peptidecombination number 8 will on have 3 peptides that the patient populationcan respond to.

FIG. 21: This figure shows the selected subset of HLA alleles fromsingle loci (Table 8) that would individually be present in between 15%and 97% of a worldwide population and together the alleles would bepresent in 99% of the worldwide population.

FIG. 22: This figure refers to the cumulated T cell responses of variouspeptide combinations. The figure shows T cell response frequencies ofpeptide combinations calculated from the actual single peptide T cellresponses and compared to the actual T cell responses determined onpeptide combinations. There is found a high correlation betweencumulated single T cell responses of each peptide in the peptidecombination and the actual T cell response of the peptide combination,thereby indicating that the T cell response of additional suggestedpeptide combinations can be estimated with high probability using thesingle peptide responses.

DETAILED DESCRIPTION

The following definitions and terminology are used herein:

The term “peptide” as used herein denotes an individual (e.g. isolated)amino acid molecule having a sequence length of about 12 to 30 aminoacid residues. A peptide as referred to herein may be a linear peptide,which does not comprise a secondary helix structure. A peptide as usedherein may be a parent peptide or a variant thereof.

The term “parent peptide” as used herein denotes an individual peptidethat represents a region of the allergen it originates from, whichregion contains at least one T cell epitope that herein is reported toproduce an in vitro T cell response in a high fraction of the donorpopulation and to have broad HLA Class II coverage. In the presentcontext, the individual peptides having an amino acid sequence of SEQ IDNOs: 9 (pep-041), 10 (pep-042), 11 (pep-043), 12 (pep-044), 42(pep-072), 254 (pep-022), 15 (pep-047), 266 (pep-123), 255 (pep-025), 17(pep-049), 46 (pep-075), 18 (pep-050), 258 (pep-122), 267 (pep-124), 20(pep-052), 49 (pep-078), 21 (pep-053), 268 (pep-130), 22 (pep-054), 23(pep-055), 52 (pep-081), 26 (pep-058), 29 (pep-061), 58 (pep-087), 251(pep-010), 252 (pep-011), 272, 71 (pep-100), 72 (pep-101), 60 (pep-089),61 (pep-090), 73 (pep-102), 249 (pep-002), 62 (pep-091), 63 (pep-092),77 (pep-106), 67 (pep-096), 271 (pep-131), 79 (pep-108), 256 (pep-031),270 (pep-126), 81 (pep-109), 269 (pep-125), 70 (pep-099) and 82(pep-110), are considered parent peptides. As shown herein, anindividual peptide derived from the same region of the allergen as theparent peptide and which overlaps with at least 15 contiguous amino acidresidues of the parent peptide also produces a T cell response in a highfraction of the donor population. Such individual peptides are thus saidto belong to the same peptide group of individual peptides as the parentpeptide.

Thus, the term “a group of peptides” or “peptide group” is meant todenote a collection of individual peptides derived from the same regionof an allergen and which have at least about 14 to 15 contiguous aminoacids overlapping with the amino acid sequence of a parent peptidedefined herein, optionally with 1, 2, or 3 modifications (e.g.substitutions or deletions of amino acid residues within the 14 to 15contiguous amino acids). A group of peptides therefore contains one ormore parent peptides defined herein and variants of said parentpeptides. Tables 9 and 10 provide examples of parent peptides andvariants thereof.

As used herein an “epitope” refers to a region or part of an antigen,such as a peptide disclosed herein, that elicits an immune response whenadministered to a subject. An epitope may be a T cell epitope, i.e., anepitope that elicits, stimulates, induces, promotes, increases orenhances a T cell activity, function or response. For example a Th2 cellepitope. Any peptide or combination of peptides of interest can beanalyzed to determine whether they include at least one T cell epitopeusing any number of assays (e.g. T cell proliferation assays, lymphokinesecretion assays, T cell non-responsiveness studies, etc.).

The term “allergen” refers to an antigen which elicits, induces,stimulates, or enhances an immune response by a cell of the immunesystem of an exposed animal (e.g., human). An antigen is an allergenwhen the specific immune response is the development of enhancedsensitivity or a hypersensitivity to the antigen, but the antigen itselfis not typically innately harmful. An allergen is therefore a particulartype of antigen that can cause development of enhanced or increasedsensitivity or hypersensitivity in a subject. For example, an allergencan elicit production of IgE antibodies in predisposed subjects. HLAalleles as disclosed herein uses a simpler notation, such as DRB1_0101or DPA10102-DPB10101, respectively instead of the official HLAnomenclature, as presented at the web site “HLANomenclature”<url:http://hla.alleles.org/>. The amino acid sequence ofan expressed HLA allele can be identified as HLA-X*YY:ZZ where X denotesa specific locus, e.g. the DRB1 locus. YY is a two digit numberreferring to the allele group, formerly defined by the serotype. ZZ is atwo or three digit number (herein always two digits) defining thespecific HLA protein. Thus a specific beta chain may be referred to ase.g., HLA-DRB1*01:01, and a specific alpha-beta chain pair be denoted asHLA-DPA1*02:01-HLA-DPB1*01:01.

Compositions (Peptide Combinations)

As disclosed herein, compositions (e.g. peptide combinations) of theinvention comprise at least three peptides selected from at least threeof peptide groups 1 to 26 disclosed herein. In other embodiments, thecomposition comprises at least four peptides, wherein the compositioncomprises peptides selected from at least 3 or 4 of the peptide groups 1to 26. In still other embodiments, the composition comprises at leastfive peptides, wherein the composition comprises peptides selected fromat least 3, 4 or 5 of the peptide groups 1 to 26. Additional peptides inthe compositions as disclosed herein is preferably selected from one ormore peptide groups from which there is no other peptide in thecomposition. In some preferred embodiments, the peptides in the hereindisclosed compositions are all from different peptide groups. In stillother embodiments, a composition as disclosed herein comprises a maximumof three peptides selected from each of three different peptide groups,a maximum of four peptides selected from each of four different peptidegroups, a maximum of five peptides selected from each of five differentpeptide groups, a maximum of six peptides selected from each of sixdifferent peptide groups, or a maximum of seven peptides selected fromeach of seven different peptide groups. Thus, a composition of theinvention may comprise a maximum of three, four, five, six or sevenpeptides.

By the present invention, there are provided several peptidecombinations able to produce an in vitro T cell response in a highfraction of the donor population (see e.g. FIG. 9a , Table 14). Incertain embodiments, the peptide combinations are assembled using acollection of peptides from peptide groups 3, 4, 5, 6, 7, 9, 10, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 24, 25 and 26. Therefore, in someembodiments, the at least three peptides are selected from at leastthree of the following peptide groups 3, 4, 5, 6, 7, 9, 10, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 24, 25 and 26.

Compositions of the invention may, but not necessarily, comprisepeptides from an allergen of both the house dust mite speciesDermatophagoides farinae and Dermatophagoides pteronyssinus. Also, thepeptide combinations may, but not necessarily, comprise individualpeptides derived from both a house dust mite (HDM) group 1 allergen(e.g. Der p 1 and/or Der f 1) and a house dust mite (HDM) group 2allergen (e.g. Der p 2 and/or Der f 2). In some embodiments of theinvention, the composition comprises at least three peptides, whereinone of the peptides derives from Der p 1 or Der f 1 and another peptidederives from Der p 2 or Der f 2.

Hence in some embodiments, at least one peptide is selected from any oneof the peptide groups 1-17, these groups representing peptides derivedfrom Der p 1 and/or Der f 1, for example a peptide consisting of anamino acid sequence selected from any one of SEQ ID NOs: 251 (pep-010),252 (pep-011), 253 (pep-012), 254 (pep-022), 255 (pep-025), 9 (pep-041),10 (pep-042), 11 (pep-043), 12 (pep-044), 17 (pep-049), 18 (pep-050), 20(pep-052), 21 (pep-053), 22 (pep-054), 23 (pep-055), 26 (pep-058), 29(pep-061), 42 (pep-072), 46 (pep-075), 49 (pep-078), 52 (pep-081), 58(pep-087), 258 (pep-122), 266 (pep-123), 267 (pep-124), 268 (pep-130),259 (pep-203B), 90, 98, 99, 280, 102, 161, 281, 282, 103, 105, 106, 283,111, 112, 284, 114, 115, 173, 174, 285, 117, 176, 120, 121, 180, 128,129, 272, 187, 188, 273, 191, 133, 274, 140 and 199, or a variantthereof.

In some embodiments, at least one peptide is selected from any one ofthe peptide groups 18-26, these groups representing peptides derivedfrom Der p 2 and/or Der f 2, for example a peptide consisting of anamino acid sequence selected from any one of SEQ ID NOs: 249 (pep-002),253 (pep-012), 256 (pep-031), 238 (pep-066), 60 (pep-089), 61 (pep-090),62 (pep-091), 63 (pep-092), 67 (pep-096), 70 (pep-099), 71 (pep-100) 72(pep-101), 73 (pep-102), 77 (pep-106), 79 (pep-108), 81 (pep-109), 82(pep-110), 269 (pep-125), 270 (pep-126), 271 (pep-131), 264 (pep-26B),226, 275, 227, 205, 206, 229, 230, 192, 276, 277, 208, 233, 278, 210,234, 242, 243, 279, 221, 245, 246, 283, 223, 247, 224 and 248, or avariant thereof. In some embodiments at least one peptide is selectedfrom any one of the peptide groups 1-17 and at least one peptide isselected from any one of the peptide groups 18-26.

As disclosed herein, compositions of the invention provide high HLAClass II coverage to a worldwide population. Therefore, in certainembodiments, the peptides of the peptide combination bind collectivelyto the majority of the alleles disclosed in Table 8 or Table 17. Forexample, a peptide combination of the invention may collectively bind toat least 20 of the 28 HLA alleles in the group consisting ofDPA10201-DPB10101, DPA10103-DPB10201, DPA10103-DPB10301,DPA10103-DPB10401, DPA10103-DPB10402, DPA10202-DPB10501,DPA10201-DPB11401, DQA10501-DQB10201, DQA10501-DQB10301,DQA10301-DQB10302, DQA10401-DQB10402, DQA10101-DQB10501,DQA10102-DQB10602, DRB1_0101, DRB1_0301, DRB1_0401, DRB1_0405,DRB1_0701, DRB1_0901, DRB1_1101, DRB1_1201, DRB1_1302, DRB1_1501,DRB3_0101, DRB3_0202, DRB4_0101 and DRB5_0101. To increase the HLA ClassII coverage, the peptides of a peptide combination may collectively bindto at least 21, 22, 23, 24, 25, 26, 27 or 28 of the 28 alleles. In otherterms, a peptide combination of the invention may collectively bind toat least 70%, such as at least 75%, 80%, 85%, 88%, 90%, 92%, 94%, 95%,96%, 97% or 98% of the HLA alleles consisting of the group ofDPA10201-DPB10101, DPA10103-DPB10201, DPA10103-DPB10301,DPA10103-DPB10401, DPA10103-DPB10402, DPA10202-DPB10501,DPA10201-DPB11401, DQA10501-DQB10201, DQA10501-DQB10301,DQA10301-DQB10302, DQA10401-DQB10402, DQA10101-DQB10501,DQA10102-DQB10602, DRB1_0101, DRB1_0301, DRB1_0401, DRB1_0405,DRB1_0701, DRB1_0901, DRB1_1101, DRB1_1201, DRB1_1302, DRB1_1501,DRB3_0101, DRB3_0202, DRB4_0101 and DRB5_0101.

The HLA Class II coverage may be determined using numerous alleles. Forexample, the peptide combination may collectively bind to at least 70%of the 83 HLA alleles disclosed in Table 17, such as at least 75%, 80%,85%, 88%, 90%, 92%, 94%, 95%, 96%, 97% or 98% of the HLA allelesconsisting of the group of DRB1_0101, DRB1_0102, DRB1_0103, DRB1_0301,DRB1_0302, DRB1_0307, DRB1_0401, DRB1_0402, DRB1_0403, DRB1_0404,DRB1_0405, DRB1_0406, DRB1_0407, DRB1_0408, DRB1_0410, DRB1_0411,DRB1_0417, DRB1_0701, DRB1_0801, DRB1_0802, DRB1_0803, DRB1_0804,DRB1_0806, DRB1_0809 DRB1_0811, DRB1_0901, DRB1_1001 DRB1_1101,DRB1_1102, DRB1_1103 DRB1_1104, DRB1_1106, DRB1_1110 DRB1_1111,DRB1_1128, DRB1_1201 DRB1_1202, DRB1_1301 DRB1_1302, DRB1_1303,DRB1_1304, DRB1_1305, DRB1_1307, DRB1_1311 DRB1_1312, DRB1_1323,DRB1_1331, DRB1_1401, DRB1_1402, DRB1_1403, DRB1_1404, DRB1_1405,DRB1_1406, DRB1_1407, DRB1_1418, DRB1_1419, DRB1_1424, DRB1_1501,DRB1_1502, DRB1_1503, DRB1_1504, DRB1_1506, DRB1_1519, DRB1_1601DRB1_1602, DRB1_1607, DRB3_0101, DRB3_0202, DRB4_0101, DRB5_0101DPA10103-DPB10201, DPA10103-DPB10301, DPA10103-DPB10401,DPA10103-DPB1040, DPA10201-DPB10101, DPA10201-DPB11401,DPA10202-DPB10501, DQA10101-DQB10501, DQA10102-DQB10602,DQA10301-DQB10302, DQA10401-DQB10402, DQA10501-DQB10201 andDQA10501-DQB10301.

To assemble peptide combinations with high HLA Class II coverage, onemay consider combining at least three peptides independently selectedfrom peptides having high worldwide HLA class II coverage, for examplepeptides with the rating “A” shown in Table 12. Those peptides areregarded as “high T cell responders” and also possess high HLA class IIcoverage.

Thus, in some embodiments, the at least three peptides are selected fromat least three of the peptide groups 4, 5, 6, 9, 10, 13, 14, 15, 16, 17,20, 21, 24, 25 and 26. Exemplary peptide combinations of suchembodiments are shown in Table 14 (peptide combinations 3, 4, 5, 6, 7,9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 23, 24, 25, 17, 17a, 17b,17c, 17d, 17f, 17p, 17l, 17q, 17s, 17t, 17u, 17v and 17x). As shownherein (e.g. FIGS. 9a, 9b, 9f and 9j ), these peptide combinations haveT cell responders in more than 65% of the donor population. Notably, thepeptide combinations number 21 and 22, which do not comprise individualpeptides from at least three of the peptide groups selected from 4, 5,6, 9, 10, 13, 14, 15, 16, 17, 20, 21, 24, 25 and 26 produce T cellresponses in considerable fewer donors. Peptide combination number 22comprises an individual peptide from each of the peptide groups 7, 20and 17.

Therefore, in some embodiments the composition does not comprise apeptide from peptide group 7, a peptide from peptide group 20 or apeptide from peptide group 17. In particularly, the composition does notcomprise as two of the peptides, a peptide from peptide group 7 and apeptide from peptide group 20. Furthermore in some embodiments, thecomposition does not comprise as three of the peptides, a peptide frompeptide group 7, a peptide from peptide group 20 and a peptide frompeptide group 17.

Furthermore, some peptides are poorly soluble in aqueous solution, forexample in solutions having a target pH in the range of pH 4 to 8 or aredifficult to synthesize. Therefore, to assemble peptide combinations ofthe invention not having particular constraints with respect tosolubility and manufacturability, a composition may comprise at leastthree peptides selected from any of the “first choice peptides” as setout in Table 15. Therefore, in some embodiments, the at least threepeptides are selected from at least three of the peptide groups 9, 10,13, 14, 16, 17, 20, 21, 24, 25 and 26.

Compositions may comprise at least four, five, six or seven peptidesselected from at least four, five, six or seven of the peptide groups 1to 26. Thus, a composition comprising the at least three peptides maycomprise an additional peptide (e.g. one, two, three or more peptides)selected from any of the peptide groups 1-26, preferably from whichgroup there is no other peptide in the composition. Thus, an additionalpeptide may be selected from any one of the group of peptides 1-26 thatare not represented in the composition. For example, in someembodiments, a composition may comprise at least four peptides, whereinthe composition comprises peptides selected from at least three or fourof the peptide groups 1 to 26, for example selected from at least threeor four of the peptide groups 4, 5, 6, 9, 10, 13, 14, 15, 16, 17, 20,21, 24, 25 and 26, for example selected from at least three or four ofthe peptide groups 9, 10, 13, 14, 16, 17, 20, 21, 24, 25 and 26. In someembodiments, a composition may comprise at least five peptides, whereinthe composition comprises peptides selected from at least three, four orfive of the peptide groups 1 to 26, for example selected from at leastthree, four or five of the peptide groups 4, 5, 6, 9, 10, 13, 14, 15,16, 17, 20, 21, 24, 25 and 26, for example selected from at least three,four or five of the peptide groups 9, 10, 13, 14, 16, 17, 20, 21, 24, 25and 26. For example, the peptide combinations may be assembled byselecting a first, second or third peptide from any of the peptidesdisclosed in Table 15.

In some embodiments, the composition comprises as one of the peptides apeptide from peptide group 26 (e.g. parent peptide pep-110 or a variantthereof). Exemplary peptide combinations are combination numbers 3, 4,5, 9, 10, 13, 16, 18, 19, 20, 23, 25, 17, 17a, 17b, 17c, 17d, 17f, 17p,17l, 17q, 17s, 17t, 17v and 17x shown in Table 14. Such compositions mayadditionally comprise as one of the peptides a peptide derived from aHDM group 1 allergen, e.g. a peptide selected from any one of thepeptide groups 1-17.

In some embodiments, the composition comprises as one of the peptides apeptide from peptide group 26 (e.g. parent peptide pep-110 or a variantthereof) and comprises as one of the peptides a peptide selected fromany one of the peptide groups 24, 17, 9 and 16. Exemplary peptidecombinations are combination numbers 3, 4, 5, 9, 10, 16, 18, 19, 20, 23,25, 17, 17a, 17b, 17c, 17d, 17f, 17p, 17l, 17q, 17s, 17t, 17v and 17xshown in Table 14. The composition may comprise one or more additionalpeptides independently selected from any of the peptide groups 1-26 fromwhich there is no other peptide in the composition, for example frompeptide groups 3, 4, 6, 9, 10, 16, 17 and 21.

In some embodiments, the composition comprises as two of the peptides, apeptide from peptide group 26 (e.g. parent peptide pep-110 or a variantthereof) and a peptide from peptide group 24 (e.g. parent peptidepep-131 or a variant thereof). Exemplary peptide combinations arecombination numbers 3, 5, 9, 17f, 17p, 17l, 17q, 17s, 17v, and 17x shownin Table 14.

In some embodiments, the composition comprises a third peptide selectedfrom any one of the peptide groups 1-17, for example selected from anyone of the peptide groups 4, 5, 6, 9, 10, 13, 14, 15, 16 and 17.

As shown herein, a composition comprising three peptides may produce a Tcell response in a high fraction of donors (FIG. 9e ). Therefore, insome embodiments, the third peptide is from peptide group 14 (e.g.parent peptide pep-130 or pep-054; or a variant thereof). Exemplarypeptide combinations are combination numbers 17f, 17p, 17q, 17s and 17vshown in Table 14.

The composition may in addition to the three peptides from each of thepeptide groups 26, 24 and 14 comprise an additional peptide selectedfrom any one of the peptide groups 1-13, 15-23 and 25, such as selectedfrom any one of the peptide groups 9, 16 and 21.

Thus, in some embodiments, a composition comprises three, four, five,six or seven peptides, wherein the composition comprises peptides fromeach of the three peptide groups 26, 24 and 14 and in addition comprisesa peptide selected from any one of the peptide groups 9, 16 and 21.

In more specific embodiments, such compositions comprise five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 24, 14, 9 and 16. For example, peptide combination 17q (shownin Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof.

Another example is peptide combination 17f (shown in Table 14) thatcomprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof.

In still some specific embodiments, the composition comprises fivepeptides, wherein the composition comprises peptides selected from eachof the five peptide groups 26, 24, 14, 9 and 21. For example, thepeptide combination 17p (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: SEQ ID NO:62 (pep-091) or a variant thereof.

Another examples is peptide combination 17s (shown in Table 14) thatcomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

In still other specific embodiments, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 24, 14, 16 and 21. For example, peptidecombination 17v (shown in Table 14) that comprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

As mentioned, in some embodiments of the invention a compositioncomprises as two of the peptides, a peptide from peptide group 26 and apeptide from peptide group 24. In some embodiments thereof, a thirdpeptide is from peptide group 9 or from peptide group 21. Exemplarypeptide combinations are combination numbers 17f, 17p, 17l, 17q, 17s,17v and 17x (shown in Table 14).

In some specific embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 24, 21, 9 and 13. For example peptidecombination number 17x (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 21 (pep-053)or a variant thereof.

In still other embodiments, a composition may comprise as two of thepeptides, a peptide from peptide group 26 and a peptide from peptidegroup 24 and a third peptide from peptide group 17 (e.g. pep-010 orpep-011; or a variant thereof). Exemplary compositions are peptidecombinations numbers 3, 5 and 9 (shown in Table 14). Thus, a compositionmay comprise at least three peptides, wherein the composition comprisesa peptide from each of the three peptide groups 3, 5 and 9. Optionally,an additional peptide is selected from any one of the peptide groups1-16, 18-23 and 25, such as peptide groups 3, 4, 6, 9, 10, 14, 16 and21. In some embodiments thereof, the additional peptide(s) is selectedfrom any one or both of the peptide groups 7 and 10. Thus, a compositionmay comprise three, four, five, six or seven peptides, wherein thecomposition comprises peptides from three of the peptide groups 26, 24and 17 and wherein an additional peptide is selected from any of thepeptide groups 7 and 10. In specific embodiments thereof, thecomposition comprises five peptides, wherein the composition comprises apeptide from each of the five peptide groups 26, 24, 17, 7 and 10.Exemplary compositions are peptide combinations number 5 (shown in Table14) and 9 (shown in Table 14). For example peptide combination number 5(shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 256(pep-031) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 252(pep-011) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 254(pep-022) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof.

Another example is peptide combination number 9 (shown in Table 14) thatcomprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 256(pep-031) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 251(pep-010) or a variant thereof

d) a parent peptide with the amino acid sequence SEQ ID NO: 254(pep-022) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof.

In still some embodiments, the composition comprises five peptides,wherein the composition comprises peptides from each of the four peptidegroups 26, 24, 17 and 10; and a peptide with the amino acid sequence SEQID NO: 117 (pep-p4) or a variant thereof. For example peptidecombination number 3 (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 256(pep-031) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 252(pep-011) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 117 or avariant thereof.

In some embodiments, the composition comprises as two of the peptides, apeptide from peptide group 26 (e.g. parent peptide pep-110 or a variantthereof) and a peptide from peptide group 17 (e.g. a parent peptideselected from any of pep-087, pep-010, pep-011, pep-061; or a variantthereof). Exemplary peptide combinations are combination numbers 3, 5,9, 16, 19 and 20 shown in Table 14.

In some embodiments, the composition comprises three peptides, whereinthe composition comprises peptides from each of the three peptide groups26, 17 and 6. For example peptide combination number 16 (shown in Table14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 251(pep-010) or a variant thereof; and

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof.

In some embodiments, the composition comprises as two of the peptides, apeptide from peptide group 26 (e.g. parent peptide pep-110 or a variantthereof) and a peptide from peptide group 9 (e.g. a parent peptideselected from any of pep-123, pep-025, pep-075 or pep-049; or a variantthereof). Exemplary peptide combinations are combination numbers 10, 18,23, 25, 17, 17c, 17f, 17p, 17l, 17q, 17s 17t and 17x shown in Table 14.In some embodiments thereof, the composition comprises five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 6, 16 and 19. For example the composition of peptidecombination number 10 (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 60 (pep-089)or a variant thereof.

In some embodiments thereof, the composition comprises five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 6, 18 and 20.

For example the composition of peptide combination number 23 (shown inTable 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 71 (pep-100)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 73 (pep-102)or a variant thereof.

In still some embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 9, 6, 12 and 21. For example, the composition ofpeptide combination number 25 (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 17(pep-049)) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 20(pep-052), or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

In still some embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 9, 16, 3 and 25. For example, the composition ofpeptide combination number 17 (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 81 (pep-109)or a variant thereof.

In still some embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 9, 16, 14 and 25. For example, the compositionof peptide combination number 17a (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 22 (pep-054)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 81 (pep-109)or a variant thereof.

In still some embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 9, 16, 3 and 21. For example, the composition ofpeptide combination number 17c (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

In still some embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 9, 16, 14 and 21. For example, the compositionof peptide combination number 17t (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

In some embodiments, the composition comprises as two of the peptides, apeptide from peptide group 26 (e.g. parent peptide pep-110 or a variantthereof) and a peptide from peptide group 16 (e.g. a parent peptidepep-058 or a variant thereof). Exemplary peptide combinations arecombination numbers 10, 17a, 17b, 17c, 17d, 17f, 17l, 17q and 17t shownin Table 14. In some embodiments thereof, the composition comprises fivepeptides, wherein the composition comprises peptides from each of thefive peptide groups 26, 16, 3, 15 and 25. For example the composition ofpeptide combination number 17b (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 52 (pep-081)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 81 (pep-109)or a variant thereof.

In some embodiments thereof, the composition comprises five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 16, 14, 15 and 21. For example the composition of peptidecombination number 17d (shown in Table 14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 22 (pep-054)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 52 (pep-081)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

As should be understood, compositions of the invention preferablycomprise only one peptide from a peptide group defined herein. However,in certain embodiments, the composition may comprise two peptides of thesame peptide group, wherein one of the peptides derives from Der p andthe other peptide of the same peptide group derives from Der f. Examplesof such compositions are peptide combinations 13, 18, 19 and 20 of Table14 that comprise two peptides from peptide group 26.

Therefore, in some embodiments, the composition comprises threepeptides, wherein the composition comprises two peptides from peptidegroup 26 and one peptide from peptide group 6. For example thecomposition of peptide combination number 18 (shown in Table 14) thatcomprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof; and

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof.

Still, in some embodiments, the composition comprises five peptides,wherein the composition comprises two peptides from peptide group 26 andone peptide from each of the three peptide groups 9, 6 and 3. Forexample the composition of peptide combination number 18 (shown in Table14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 17 (pep-049)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof.

In still some embodiments, the composition comprises five peptides,wherein the composition comprises two peptides from peptide group 26 andone peptide from each of the three peptide groups 17, 10 and 3. Forexample the composition of peptide combination number 19 (shown in Table14) that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 251(pep-010) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 18 (pep-050)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof.

In still some embodiments, the composition comprises four peptides,wherein the composition comprises two peptides from peptide group 26 andone peptide from each of the two peptide groups 17 and 10. For examplethe composition of peptide combination number 20 (shown in Table 14)that comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 251(pep-010) or a variant thereof; and

d) a parent peptide with the amino acid sequence SEQ ID NO: 18 (pep-050)or a variant thereof.

In certain embodiments, the composition comprises as one of the peptidesa peptide of peptide group 26, the composition does not comprise apeptide of any of the peptide groups 24, 17, 9 and 16, but may stillachieve high T cell responder rate and worldwide HLA Class II coverage.For example, a composition of the peptide combination number 4 of Table14. Therefore, in some embodiments, the composition comprises fourpeptides, wherein the composition comprises peptides from each of thefour peptide groups 26, 7, 10 and 20. A composition of the peptidecombination number 4 (shown in Table 14) comprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 254(pep-022) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 249(pep-002) or a variant thereof; and optionally

e) a parent peptide with the amino acid sequence SEQ ID NO: 257(pep-117) or a variant thereof.

In certain embodiments, the composition comprises as one of the peptidesa peptide of peptide group 26, but the composition does not comprise apeptide of any of the peptide groups 24, 17, 9 and 16. As shown in FIG.9a for peptide combination number 24 (shown in Table 14), such acomposition may still achieve high T cell responder rate and worldwideHLA Class II coverage. Therefore, in certain embodiments, thecomposition comprises five peptides, wherein the composition comprisespeptides from each of the five peptide groups 10, 6, 12, 18 and 20. Forexample peptide combination number 24 (shown in Table 14) thatcomprises:

a) a parent peptide with the amino acid sequence SEQ ID NO: 18 (pep-050)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 49 (pep-078)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 71 (pep-100)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 73 (pep-102)or a variant thereof.

It should be understood that compositions comprising three peptides,such as four peptides, such as five peptides, may comprise an additionalpeptide selected from any one of the peptide groups 1 to 26, whereinoptionally the additional peptide(s) is from a peptide group from whichthere is no other peptide in the composition, thus the additionalpeptide is of any of the peptide groups 1 to 26 that is not representedin the peptide combination, for example from peptide groups 3, 4, 6, 10,16, and 21. In certain embodiments, the additional peptide is from thesame peptide group as another peptide of the composition, wherein theadditional peptide is derived from another allergen species selectedfrom Der p and Der f. For example, the composition may comprise one,two, three four or more additional peptides. For example, in certainembodiments the compositions may comprise up to four peptides, up tofive peptides, up to six peptides, up to seven peptides.

The present invention has been exemplified with numerous peptidecombinations shown in Table 14, but several other peptide combinationsmay be provided by substituting one of the peptides of the peptidecombinations shown in Table 14 with another peptide from the samepeptide group, i.e. a variant of the parent peptide or one of the otherparent peptides or variants thereof also included in the same peptidegroup. Furthermore, one peptide from one peptide group may besubstituted with a peptide from another group. For example, a peptidefrom a peptide group may be substituted with a peptide from anotherpeptide group that has the same functionality, for example thefunctionality that the substitute peptide binds to the same orsubstantially the same group of HLA Class II alleles that the originalpeptide binds to. The ability of a peptide to bind HLA Class II allelesmay be determined by a competitive MHC class II binding assay (Forexample as disclosed in Example 9) that determines the ability of apeptide to displace a known control binder from a human MHC class IIallotype, for example the allotypes shown in Tables 8 or 17 herein.Thus, in some embodiments, a substitute peptide binds to the same,substantially the same or at least 70%, 75%, 80%, such as at least 85%,88%, 90%, 92%, 94%, 95%, 96%, 97% or 98%, or more of the alleles bindingto the peptide to be substituted, for example where the binding isdetermined by in-vitro binding assay or predicted binding to the allelesconsisting of the group of DPA10201-DPB10101, DPA10103-DPB10201,DPA10103-DPB10301, DPA10103-DPB10401, DPA10103-DPB10402,DPA10202-DPB10501, DPA10201-DPB11401, DQA10501-DQB10201,DQA10501-DQB10301, DQA10301-DQB10302, DQA10401-DQB10402,DQA10101-DQB10501, DQA10102-DQB10602, DRB1_0101, DRB1_0301, DRB1_0401,DRB1_0405, DRB1_0701, DRB1_0901, DRB1_1101, DRB1_1201, DRB1_1302,DRB1_1501, DRB3_0101, DRB3_0202, DRB4_0101 and DRB5_0101 or optionallythose listed in Table 17.

For example peptide 041 (SEQ ID NO: 9) is able to bind the allelesDRB1_1302, DRB3_0101, DRB3_0202, DQA10501-DQB10201 and DQA10401-DQB10402and may be replaced by any of the peptides 011, 010 and 075 (SEQ ID NOs:252, 251 and 46, respectively) that binds to at least the same allelesas peptide 041 as shown in Table 16a.

In the same way, it may be that a:

-   -   parent peptide with an amino acid sequence of SEQ ID NO: 17        (pep-058) may be substituted with parent peptide with an amino        acid sequence of SEQ ID NOs: 22 (pep-054), 255 (pep-025) or 49        (pep-078);    -   parent peptide with an amino acid sequence of SEQ ID NO: 46        (pep-075) may be substituted with parent peptide with amino acid        sequence SEQ ID NOs: 255 (pep-025), 285, 17 (pep-049), 20        (pep-052), 22 (pep-054), 21 (pep-053), 49 (pep-078) or 266        (pep-123);    -   parent peptide with an amino acid sequence of SEQ ID NO: 82        (pep-110) may be substituted with parent peptide with an amino        acid sequence of SEQ ID NOs: 253 (pep-012), 70 (pep-099), 264        (pep-HDM26B), 269 (pep-125), 224 or 248;    -   parent peptide with an amino acid sequence of SEQ ID NO: 268        (pep-130) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 255 (pep-025), 12 (pep-044), 22        (pep-054) or 21 (pep-053);    -   parent peptide with an amino acid sequence of SEQ ID NO: 271        (pep-131) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 256 (pep-031), 81 (pep-109) or 67        (pep-096);    -   parent peptide with an amino acid sequence of SEQ ID NO: 81        (pep-109) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 256 (pep-031), 67 (pep-096) or 271        (pep-131);    -   parent peptide with an amino acid sequence of SEQ ID NO: 17        (pep-049) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 46 (pep-075) or 266 (pep-123);    -   parent peptide with an amino acid sequence of SEQ ID NO: 22        (pep-054) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NO: 255 (pep-025), 12 (pep-044), 21        (pep-053), 26 (pep-058), 46 (pep-075) or 268 (pep-130);    -   parent peptide with an amino acid sequence of SEQ ID NO: 67        (pep-096) may be substituted with parent peptide with an amino        acid sequence of SEQ ID NO: 256 (pep-031), 81 (pep-109) or 271        (pep-131);    -   parent peptide with an amino acid sequence of SEQ ID NO: 12        (peptide 044) may be substituted with a parent peptide with an        amino acid sequence of SEQ ID NOs: 22 (pep-054), 268 (pep-130)        or 283;    -   parent peptide with an amino acid sequence of SEQ ID NO: 15        (pep-050) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 254 (pep-022), 26 (pep-058), 274,        52 (pep-081), 258 (pep-122) or 267 (pep-124);    -   parent peptide with an amino acid sequence of SEQ ID NO: 256        (pep-031) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 81 (pep-109), 271 (pep-131), 67        (pep-096) or 270 (pep-126);    -   parent peptide with an amino acid sequence of SEQ ID NO: 251        (pep-010) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 252 (pep-011), 58 (pep-087) or 29        (pep-061);    -   parent peptide with an amino acid sequence of SEQ ID NO; 258        (pep-122) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 18 (pep-050), 52 (pep-081) or 267        (pep-124);    -   parent peptide with an amino acid sequence of SEQ ID NO: 253        (pep-012) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 256 (pep-031), 70 (pep-099), 81        (pep-109), 82 (pep-110), 269 (pep-125);    -   parent peptide with an amino acid sequence of SEQ ID NO: 73        (pep-102) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 249 (pep-002), 60 (pep-089), 61        (pep-090), 276, 277 or 82 (pep-110);    -   parent peptide with an amino acid sequence of SEQ ID NO: 70        (pep-099) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 253 (pep-012), 264 (pep-26B), 82        (pep-110) or 269 (pep-125);    -   parent peptide with an amino acid sequence of SEQ ID NO: 52        (pep-081) may be substituted with a parent peptide with an amino        acid sequence of SEQ ID NOs: 250 (pep-009), 254 (pep-022), 10        (pep-042), 18 (pep-050), 258 (pep-122) or 23 (pep-055).

In specific embodiments, parent peptide pep-075 (SEQ ID NO: 46) ofpeptide group 9 may be substituted with parent peptide pep-123 (SEQ IDNO: 266) or a variant thereof, and parent peptide pep-054 (SEQ ID NO:22) may be substituted with parent peptide pep-091 SEQ ID NO: 62) or avariant thereof.

Variants of Parent Peptides (Variants Thereof)

A parent peptide described herein may contain one or more modifications,which optionally may result in greater or less activity or function, forexample in the ability to elicit, stimulate or induce an in vitro immuneresponse (e.g. T cell proliferation or T cell cytokine production); inthe ability to bind HLA Class II alleles; in the ability to induce orenhance immunological tolerance to a relevant antigen, e.g. a house dustmite allergen, such as Der p 1, Der f1, Der p 2 and/or Der f 2; or inthe ability to dissolve in solvents e.g. in an aqueous solution.

A modification may include one or more deletions of amino acid residuesfrom the N- and/or C-terminal end of the parent peptide, one or moreadditions of amino acid residues to the N- and/or C-terminal of theparent peptide and/or one or more amino acid substitutions, additions ordeletions within the amino acid sequence of the parent peptide.

Typically, a longer variant of the parent peptide may be up to 60 aminoacids in length, for example up to 55, 50, 45, 40, 35, 30, 28, 25, 24,or 22 amino acids in length. More typically, a longer variant peptide isup to about 30 amino acids in length, such as up to 25 amino acids inlength. The longer variant may comprise the amino acid sequence of aparent peptide disclosed herein, or an amino acid sequence having atleast 65% identity or similarity over the length of the amino acidsequence of the parent peptide or a fragment thereof, such as over atleast 12 contiguous amino acids, for example over at least 13, 14, 15,16, 17, 18, 19, 20 contiguous amino acids of the parent peptide or overthe length of the parent peptide. Typically, the longer variantcomprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%or 95% identity or similarity over the length of the amino acid sequenceof the parent peptide or over at least 12 contiguous amino acids, forexample over at least 13, 14, 15, 16, 17, 18, 19 or 20 contiguous aminoacids of the parent peptide. Therefore, in some embodiments, a variantof the parent peptide is a longer peptide up to 30 amino acid residuesin length that comprises one or more additional amino acid residues atthe N- and/or C-terminal end than the parent peptide or comprises anamino acid sequence having at least 80% identity over at least 14contiguous amino acids of the parent peptide, such as over at least 15,16, 17, 18 contiguous amino acids of the parent peptide.

A variant of the parent peptide may also include a fragment of a parentpeptide disclosed herein. A fragment of the parent peptide can have oneor more amino acids less than the parent peptide, either comprisingdeletions from within the amino acid sequence of the parent peptideand/or amino acid deletions from the N- and/or C-terminus of the parentpeptide. Typically, a fragment will have a length of at least 12 aminoacids, for example at least 13, 14, 15, 16 or 17 amino acids, and willhave at least 65% identity or similarity over the length of thefragment, or over the length of at least 12 contiguous amino acids ofthe parent peptide, when aligned with the parent peptide. In someembodiments, the percentage identity or similarity is at least 70%, 75%,80%, 85%, 90% or 95% over the length of the fragment, or over at least12, 13, 14 or 15 contiguous amino acids of the parent peptide.Therefore, in some embodiments, a variant thereof may be a shorterpeptide comprising an amino acid sequence having at least 80% identityover at least 14 contiguous amino acids of the parent peptide, such asover at least 15, 16, 17, 18 contiguous amino acids of the parentpeptide. Examples of fragments of parent peptides disclosed herein maybe selected from SEQ ID NOs: 90, 102, 161, 103, 105, 106, 111, 114, 115,173, 174, 117, 176, 120, 121, 180, 128, 187, 188, 191, 133, 192, 199,226, 227, 205, 229, 206, 230, 208, 233, 210, 234, 242, 243, 221, 245,246, 283, 166, 223, 247, 224 and 248.

As mentioned, a variant of a parent peptide may comprise additionalamino acids or may consist of a fragment of the parent peptide. Thus, avariant of a parent peptide may consist of 12-30 amino acids, forexample 13-30, 14-30, 15-30, 16-30, 12-28, 13-28, 14-28, 15-28, 16-28,13-26, 14-26, 15-26, 16-26, 13-25, 14-25, 15-25, 15-25, 13-24, 14-24,15-24, 16-24, 3-22, 14-22, 15-22, 16-22, 13-20, 14-20, 15-20, 16-20amino acids, such as particularly 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids.

Moreover, a variant of a parent peptide may comprise an amino acidsequence having at least 65% sequence identity or similarity over atleast 14 contiguous amino acids of the parent peptide sequence,optionally wherein the percent sequence identity or similarity is atleast 70% 80%, 85%, 90% or 95% over at least 15 contiguous amino acidsof the parent peptide sequence, such as over at least 16, 17, 18 or 20contiguous amino acids of the parent peptide sequence.

In some embodiments, the variant of the parent peptides consists of14-30 amino acids residues and comprises an amino acid sequence havingat least 80% sequence identity or similarity over at least 14 contiguousamino acids of the parent peptide. In other embodiments, the variantconsists of 15-30 amino acids residues and comprises an amino acidsequence having at least 80% sequence identity or similarity over atleast 15 contiguous amino acids of the parent peptide. For example, thepercent identity or similarity may be at least 85%, such as at least 90%or 95% over at least 14 contiguous amino acids, for example over atleast 15, 16, 17, or 18 contiguous amino acids of the parent sequence.Thus, in such embodiments, the variant consists of 14-30 amino acidresidues, such as 15-30 amino acid residues, wherein one, two or threeamino acid residues within at least 14, such as at least 15, 16, 17 or18 contiguous amino acids of the parent peptide are substituted.

In particular embodiments, the variant is a peptide consisting of 17-30amino acids and comprises an amino acid sequence having at least 80%,such as at least 85%, 90% or 95% identity or similarity over at least 14or 15 contiguous amino acids of the parent sequence.

In still other particular embodiments, the variant is a peptideconsisting of 15-25 amino acids and comprises an amino acid sequencehaving at least 80% identity or similarity over at least 14 or 15contiguous amino acids of the parent sequence.

In still other particular embodiments, the variant is a peptideconsisting of 16-25 amino acids and comprises an amino acid sequencehaving at least 80% identity or similarity over at least 14 or 15contiguous amino acids of the parent sequence.

In further embodiments, the at least 80% identity or similarity is overat least 16, 17, 18 or 19 contiguous amino acids of the parent peptidesequence and the percent identity or similarity may be at least is 85%,such as at least 90% or 95% over at least 16, 17, 18 or 19 contiguousamino acids of the parent peptide sequence.

The term “identity” and “identical” and grammatical variations thereof,as used herein, mean that two or more referenced entities are the same(e.g., amino acid sequences).

Thus, where two peptides are identical, they have the same amino acidsequence. The identity can be over a defined area, e.g. over at least12, 13, 14, 15 or 16 contiguous amino acids of the parent peptidesequence, optionally wherein the alignment is the best fit with gapspermitted.

For example, to determine whether a variant peptide has at least 80%similarity or identity over at least 15 contiguous amino acid residuesof the parent peptide sequence, the variant peptide may be aligned withthe parent peptide and the percent identity calculated with respect tothe identical amino acid residues found within the amino acid sequenceof the variant peptide that overlaps with the 15 contiguous amino acidsof the parent peptide sequence.

Identity can be determined by comparing each position in alignedsequences. A degree of identity between amino acid sequences is afunction of the number of identical or matching amino acids at positionsshared by the sequences, i.e. over a specified region. Optimal alignmentof sequences for comparisons of identity may be conducted using avariety of algorithms, as are known in the art, including the ClustalOmega program available at the URL:http://www.ebi.ac.uk/Tools/msa/clustalo/, the local homology algorithmof Smith and Waterman, 1981, Adv. Appl. Math 2: 482, the homologyalignment algorithm of Needleman and Wunsch, 1970, J. Mol. Biol. 48:443,the search for similarity method of Pearson and Lipman, 1988, Proc.Natl. Acad. Sci. USA 85: 2444, and the computerized implementations ofthese algorithms (such as GAP, BESTFIT, FASTA and TFASTA in theWisconsin Genetics Software Package, Genetics Computer Group, Madison,Wis., U.S.A.). Sequence identity may also be determined using the BLASTalgorithm, described in Altschul et al., 1990, J. Mol. Biol. 215:403-10(using the published default settings). Software for performing BLASTanalysis may be available through the National Center for BiotechnologyInformation (through the internet at the URL,http://www.ncbi.nlm.nih.gov/). Such algorithms that calculate percentsequence identity (homology) generally account for sequence gaps andmismatches over the comparison region or area. For example, a BLAST(e.g., BLAST 2.0) search algorithm (see, e.g., Altschul et al., J. Mol.Biol. 215:403 (1990), publicly available through NCBI) has exemplarysearch parameters as follows: Mismatch −2; gap open 5; gap extension 2.For polypeptide sequence comparisons, a BLASTP algorithm is typicallyused in combination with a scoring matrix, such as PAM100, PAM 250,BLOSUM 62 or BLOSUM 50. FASTA (e.g., FASTA2 and FASTA3) and SSEARCHsequence comparison programs are also used to quantitate the extent ofidentity (Pearson et al., Proc. Natl. Acad. Sci. USA 85:2444 (1988);Pearson, Methods Mol Biol. 132:185 (2000); and Smith et al., J. Mol.Biol. 147:195 (1981). Programs for quantitating protein structuralsimilarity using Delaunay-based topological mapping have also beendeveloped (Bostick et al., Biochem Biophys Res Commun. 304:320 (2003)).

The term “similarity” and “similar” and grammatical variations thereof,as used herein, mean that an amino acid sequence contains a limitednumber of conservative amino acid substitutions compared to a peptidereference sequence, e.g. the variant peptide versus the parent peptide.A variety of criteria can be used to indicate whether amino acids at aparticular position in a peptide are similar. In making changes,substitutions of like amino acid residues can be made on the basis ofrelative similarity of side-chain substituents, for example, their size,charge, hydrophobicity, hydrophilicity, and the like, and suchsubstitutions may be assayed for their effect on the function of thepeptide by routine testing.

Substitutions may be conservative or non-conservative amino acidsubstitutions. A “conservative substitution” is the replacement of oneamino acid by a biologically, chemically or structurally similarresidue. Biological similarity means that the substitution does notdestroy a biological activity, e.g. T cell reactivity or HLA coverage.Structural similarity means that the amino acids have side chains withsimilar length, such as alanine, glycine and serine, or a similar size.Chemical similarity means that the residues have the same charge, or areboth either hydrophilic or hydrophobic. For example, a conservativeamino acid substitution is one in which an amino acid residue isreplaced with an amino acid residue having a similar side chain, forexample amino acids with basic side chains (e.g., lysine, arginine,histidine); acidic side chains (e.g., aspartic acid, glutamic acid);uncharged polar side chains (e.g., glycine, asparagine, glutamine,serine, threonine, tyrosine, cysteine, histidine); nonpolar side chains(e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine,methionine, tryptophan); beta-branched side chains (e.g., threonine,valine, isoleucine), and aromatic side chains (e.g., tyrosine,phenylalanine, tryptophan). Particular examples include the substitutionof one hydrophobic residue, such as isoleucine, valine, leucine ormethionine, for another, or the substitution of one polar residue foranother, such as the substitution of arginine for lysine, glutamic acidfor aspartic acid, or glutamine for asparagine, serine for threonine,and the like. Proline, which is considered more difficult to classify,shares properties with amino acids that have aliphatic side chains(e.g., Leu, Val, Ile, and Ala). In certain circumstances, substitutionof glutamine for glutamic acid or asparagine for aspartic acid may beconsidered a similar substitution in that glutamine and asparagine areamide derivatives of glutamic acid and aspartic acid, respectively.

A parent peptide disclosed herein is derived from the allergen isoformsDer p 1.0105, Der f 1.0101, Der p 2.0101 or Der f 2.0103, whereas atypical variant peptide may be derived from the same stretch found inanother isoform of the same allergen shown in Table 1. Thus, the aminoacid sequence of a parent peptide derived from one isoform of anallergen (e.g. isoform Der p 1.0105) may be substituted with one, two,three or four amino acid residues derived from another isoform of thesame allergen (e.g. isoform Derp1.0101), where the amino acid residueshave the same position number in the two isoforms.

As mentioned, a variant of a parent peptide disclosed herein maycomprise one or more additional amino acid residues at the N- and/orC-terminal end than the parent peptide. Such amino acid residues may benaturally occurring amino acids or non-naturally occurring amino acids.In some embodiments, the one or more additional amino acids are the sameamino acid or amino acid sequence flanking the N- and/or C-terminal endsof the parent peptide when aligned with the amino acid sequence of theallergen isoform it is present in, based upon or derived from or isaligned with another isoform of the same allergen. Thus, additionalamino acids may be the amino acids flanking the N- and/or C-terminalends of the parent peptide when aligned to Der p 1, Der f 1, Der p 2 orDer f 2. For example, wherein a peptide derives from Derp1.0105, theadditional amino acids may be the amino acids flanking the N- and/orC-terminal ends of the peptide when aligned to Derp1.0105 or anotherisoform thereof set out in Table 1. Likewise, peptides derived fromDerf1.0101, Derp2.0101 or Derf2.0103 may comprise additional amino acidsflanking the N- and/or C-terminal ends of the peptide when aligned toDerf1.0101 or an isoform thereof, Derp2.0101 or an isoform thereof,Derf2.0103 or an isoform thereof, respectively.

Various isoforms are shown in Table 1. For example, an isoform of Der p1 may be selected from any of the isoforms with amino acid sequence withSEQ ID Nos: 287-311, an isoform of Der f 1 may be selected from any ofthe isoforms with amino acid sequence with SEQ ID Nos: 312-322, anisoform of Der p 2 may be selected from any of the isoforms with aminoacid sequence with SEQ ID Nos: 323-337 and an isoform of Der f 2 may beselected from any of the isoforms with amino acid sequence with SEQ IDNos: 338-354.

A variant peptide may include a number of modifications compared to theparent peptide, for example to increase or decrease physical or chemicalproperties of the parent peptide, for example to decrease its ability toresist oxidation, to improve or increase solubility in aqueous solution,to decrease aggregation, to decrease synthesis problems, etc.

Accordingly, in some embodiments of the invention, a variant of a parentpeptide comprises:

a) one or more (e.g. 1, 2, or 3) amino acid substitutions in the parentpeptide sequence, for example a glutamate residue at the N-terminus ofthe parent peptide may be replaced with pyroglutamate and/or one or morecysteine residues in the parent peptide may be replaced with serine or2-aminobutyric acid; and/or

b) one or more amino acid additions (e.g. 1, 2, 3, 5, 4, 6, 7, 8) to theparent peptide sequence, for example wherein the variant comprises oneor more (e.g. 1, 2, 3, or 4) lysine residue(s) and/or one or more (e.g.1, 2, 3, or 4) arginine residue(s) and/or one or more positively chargedresidues added at the N- and/or C-terminus of the parent peptide or to afragment of the parent peptide consisting of at least 14 contiguousamino acids of the parent peptide (such as at least 15 contiguous aminoacids); and/or

c) one or more amino acid deletions from the parent peptide, for examplewherein a hydrophobic residue the up to three amino acids from the N- orC-terminus of the parent peptide are deleted; and/or any two consecutiveamino acids comprising the sequence Asp-Gly up to four amino acids fromthe N- or C-terminus of the parent peptide are deleted.

Furthermore, in some embodiments, a variant of a parent peptide maycomprise one, two, three or more lysine or arginine amino acidresidue(s) added to the N- and/or C-terminus of the parent peptide thathave been extended with one or more, e.g. 1, 2, 3, 4, or 5 amino acidresidues, optionally of the wild type sequence the peptide is based uponor another wild type isoform.

Typical examples of variants of parent peptides are shown in Tables 11a,11b and 11c. Table 11a shows examples of the addition of one or moreamino acid residues from the wild type allergen isoform to a parentpeptide. Table 11b shows examples of parent peptides pep-058, pep-075,pep-123 with one or more Arginine residues added to the N- and/orC-terminus, e.g. variants with SEQ ID NOs: 274-278, 279-282 and 283-286,respectively. Table 11c shows examples of amidation of the C-terminalend of parent peptides pep-058, pep-075, pep-110, pep-130, pep-091 andpep-123.

A parent peptide or a variant peptide thereof may be derivatized. Aderivative of a peptide (also named “derivatized peptide” herein) refersto a modified form of a peptide disclosed herein, including a modifiedform of a variant thereof. Typically, a derivative is formed by reactinga functional side group of an amino acid (e.g. amino, sulfhydryl orcarboxy-group) with another molecule to form a covalent or non-covalentattachment of any type of molecule (naturally occurring or designed),such as a sugar moiety. Specific examples of derivatives of a peptideinclude glycosylation, acylation (e.g. acetylation), phosphorylation,amidation, formylation, ubiquitination and derivatization byprotecting/blocking groups and any of numerous chemical modifications.Additional specific non-limiting examples are tagged peptides, fusionpeptides, chimeric peptides including peptides having one or morenon-amino acyl groups (q.v., sugar, lipid, etc.) covalently linked tothe peptide. Typically, a derivative comprises one or moremodifications, for example selected from any of: (a) N-terminalacylation (e.g. acetylation or formylation); (b) C-terminal amidation(e.g. reaction with ammonia or an amine); (c) one or more hydrogens onthe side chain amines of arginine and/or lysine replaced with amethylene group; (d) glycosylation and/or (e) phosphorylation.

In a particular embodiment, the peptides are amidated at the C-terminalend, for example peptide pept-130 may be amidated.

In particular embodiments, a derivative comprises a fusion (chimeric)sequence of peptides, which optionally may contain an amino acidsequence having one or more molecules not normally present in areference (wild type) sequence covalently attached to the peptide aminoacid sequence. The term “chimeric” and grammatical variations thereof,when used in reference to a sequence, means that the sequence containsone or more portions that are derived from, obtained or isolated from,or based upon other physical or chemical entities.

Another particular example of a derivative is one in which a secondheterologous sequence, i.e. a heterologous functional domain, isattached to a peptide disclosed herein, (covalent or non-covalentbinding) that may confer a distinct or complementary function to apeptide disclosed herein. Heterologous functional domains are notrestricted to amino acid residues. Thus, a heterologous functionaldomain can consist of any of a variety of different types of small orlarge functional moieties. Such moieties include nucleic acid, peptide,carbohydrate, lipid or small organic compounds, such as a drug (e.g., anantiviral), a metal (gold, silver), or a radioisotope.

Linkers, such as amino acid or peptidomimetic sequences, may be insertedbetween the peptide sequence and the addition (e.g., heterologousfunctional domain) so that the two entities maintain, at least in part,a distinct function or activity. Linkers may have one or more propertiesthat may include a flexible conformation, an inability to form anordered secondary structure or a hydrophobic or charged character, whichcould promote or interact with either domain. Amino acids typicallyfound in flexible protein regions include Gly, Asn and Ser. Other nearneutral amino acids, such as Thr and Ala, may also be used in the linkersequence.

In a particular aspect of the invention, the peptides of the peptidecombination are not provided as individual peptides, but the peptidesmay be fused together or to a carrier molecule to form an isolatedmolecule. For example, the peptides may be fused to the N- andC-terminus of a surface polypeptide of a virus, e.g. a virus of thehepadnaviridae family as disclosed in international patent applicationWO12168487 A1.

A variant peptide or a derivative of a parent peptide may share the samefunctionality or activity as the parent peptide or may have improvedfunctionality or activity. For example, a variant of a parent peptidemay bind to at least 70% of the group of Class HLA II alleles that theparent peptide binds to. Thus, in some embodiments, the variant peptidebinds to the same, substantially the same or at least 75%, 80%, such asat least 82%, 85%, 88%, 90%, 92%, 95%, 98% or more, of the group of HLAClass II alleles that binds to the parent peptide, optionally whereinthis is determined under same test conditions, either using predictiontools or in-vitro binding assay. Optionally, the Class HLA II binding isdetermined with respect to a particular group of Class HLA II alleles,for example one or more or all of the following alleles:DPA1*02:01-DPB1*01:01, DPA1*01:03-DPB1*02:01, DPA1*01:03-DPB1*03:01,DPA1*01:03-DPB1*04:01, DPA1*01:03-DPB1*04:02, DPA1*02:02-DPB1*05:01,DPA1*02:01-DPB1*14:01, DQA1*05:01-DQB1*02:01, DQA1*05:01-DQB1*03:01,DQA1*03:01-DQB1*03:02, DQA1*04:01-DQB1*04:02, DQA1*01:01-DQB1*05:01,DQA1*01:02-DQB1*06:02, DRB1*01:01, DRB1*03:01, DRB1*04:01, DRB1*04:05,DRB1*07:01, DRB1*09:01, DRB1*11:01, DRB1*12:01, DRB1*13:02, DRB1*15:01,DRB3*01:01, DRB3*02:02, DRB4*01:01 and DRB5*01:01, or the allelesdisclosed in Table 8 or in Table 17. Assays for measuring Class HLA IIbinding in vitro is well known in the art and some are described hereinin Example 9.

Furthermore, a variant peptide may have one or more of the same T cellepitopes as the parent peptide. This may be determined by the ability toinduce or stimulate in vitro T cell proliferation using cultured PBMCs(peripheral blood monocytes) in response to the variant peptide comparedto the parent peptide, optionally using same test conditions, or by theability to induce or stimulate production of cytokines, (e.g. cytokines,IL-5, IL-13 and/or IL-10) from T cells (obtained from cultured PBMC's)in response to the variant peptide compared to the parent peptide, asdescribed herein in Example 3.

Therefore, in one particular embodiment, a variant of a parent peptidemay include an overlap of at least 9 amino acid residues, preferablyidentical residues, when aligned with a parent peptide of the invention.The overlap is preferably more than 9 amino acid residues, e.g. 10, 11or 12 amino acid residues or more, such as 13, 14 or 15 amino acidresidues. The core binding sequence of MHC II molecules is known to beapproximately 9 amino acids long, although MHC II molecules canaccommodate longer peptides of 10-30 residues (Murugan and Dai, 2005).Therefore, in certain embodiments, an overlap of 9 amino acids or morewith a parent sequence is sufficient for a variant to be able to share aT cell epitope with the parent peptide.

Peptides are typically provided in the form of a salt, for example as apharmaceutically acceptable and/or a physiologically acceptable salt.For example, the salt may be an acid addition salt with an inorganicacid, an acid addition salt with an organic acid, a salt with a basicinorganic acid, a salt with a basic organic acid, a salt with an acidicor basic amino acid or a mixture thereof. Typical examples of an acidaddition salts with an inorganic acid are selected from any of the saltswith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, or the like. An acid salt with an organic acid may beselected from any of the salts with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, or the like. Salts with an inorganic basemay be selected from a salt of an alkali metal salts such as sodiumsalts and potassium salts; alkali earth metal salts such as calciumsalts and magnesium salts; and aluminum salts and ammonium salts. Saltswith a basic organic base may be selected from any salt withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, caffeine, piperidine, and pyridine. Saltswith a basic amino acid may be selected from any salt with arginine,lysine, ornithine, or the like. Salts with an acidic amino acid may beselected from any salt with aspartic acid, glutamic acid, or the like.

In particular embodiments of the invention a salt, such as apharmaceutically acceptable salt, is an acetate salt.

Typical examples of variants of parent peptides are listed in thefollowing:

-   -   a variant of a parent peptide of peptide group 26, e.g. a        variant of any of the parent peptides with the amino acid        sequence of SEQ ID NOs: 82 (pep-110), 269 (pep-125), 70        (pep-099) and 253 (pep-012) may be a peptide with the amino acid        sequence of SEQ ID NOs: 223, 247, 224 or 248;    -   a variant of a parent peptide of peptide group 24, e.g. a        variant of any of the parent peptides with the amino acid        sequence of SEQ ID NOs: 271 (pep-131), 67 (pep-096), 79        (pep-108), 256 (pep-031) and 270 (pep-126) may be a peptide with        the amino acid sequence of SEQ ID NOs: 279 or 241;    -   a variant of a parent peptide of peptide group 2, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID NO:        280 may be a peptide with the amino acid sequence of SEQ ID NO:        98;    -   a variant of a parent peptide of peptide group 3, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID NO:        9 (pep-041) may be a peptide with the amino acid sequence of SEQ        ID NO: 99;    -   a variant of a parent peptide of peptide group 4, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID NO:        10 (pep-042) may be a peptide with the amino acid sequence of        SEQ ID NOs: 259, 102, 161, 281 or 282;    -   a variant of a parent peptide of peptide group 5, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID NO:        11 (pep-043) may be a peptide with the amino acid sequence of        SEQ ID NOs: 103, 281 or 282;    -   a variant of a parent peptide of peptide group 6, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID NO:        12 (pep-044) may be a peptide with the amino acid sequence of        SEQ ID NOs: 105, 283 or 106;    -   a variant of a parent peptide of peptide group 7, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID        NOs: 42 (pep-072) or 249 (pep-022); may be a peptide with the        amino acid sequence of SEQ ID NO: 166;    -   a variant of a parent peptide of peptide group 8, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID NO:        15 (pep-047) may be a peptide with the amino acid sequence of        SEQ ID NO: 111, 270 or 112;    -   a variant of a parent peptide of peptide group 9, e.g. a variant        of the parent peptide with the amino acid sequence of SEQ ID        NOs: 266 (pep-123), 255 (pep-025), 46 (pep-075) and 17 (pep-049)        may be a peptide with the amino acid sequence of SEQ ID NO: 271,        114, 173, 115 or 174;    -   a variant of a parent peptide of peptide group 10, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 18 (pep-050), 258 (pep-122) and 267 (pep-124) may be        a peptide with the amino acid sequence of SEQ ID NO: 117 or 176;    -   a variant of a parent peptide of peptide group 12, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 20 (pep-052) or 49 (pep-078) may be a peptide with        the amino acid sequence of SEQ ID NO: 121 or 180;    -   a variant of a parent peptide of peptide group 15, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NO: 26 (pep-058) may be a peptide with the amino acid        sequence of SEQ ID NO: 133, 192, 274 or 191;    -   a variant of a parent peptide of peptide group 16, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 52 (pep-081), 23 (pep-055) and 272) may be a peptide        with the amino acid sequence of SEQ ID NO: 273, 128, 187, 129 or        188;    -   a variant of a parent peptide of peptide group 17, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 29 (pep-061), 58 (pep-087), 251 (pep-10) or 252        (pep-011) may be a peptide with the amino acid sequence of SEQ        ID NO: 140 or 199;    -   a variant of a parent peptide of peptide group 19, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NO: 72 (pep-101) and 60 (pep-089) may be a peptide with        the amino acid sequence of SEQ ID NO: 227;    -   a variant of a parent peptide of peptide group 20, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 61 (pep-090), 73 (pep-102) and 276 may be a peptide        with the amino acid sequence of SEQ ID NO: 277, 205, 229, 206 or        230;    -   a variant of a parent peptide of peptide group 21, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: SEQ ID NO: 62 (pep-091) may be a peptide with the        amino acid sequence of SEQ ID NO: 208;    -   a variant of a parent peptide of peptide group 22, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 63 (pep-092) and 278 may be a peptide with the amino        acid sequence of SEQ ID NO: 222 or 210;    -   a variant of a parent peptide of peptide group 23, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: 77 (pep-106) may be a peptide with the amino acid        sequence of SEQ ID NO: 238;    -   a variant of a parent peptide of peptide group 25, e.g. a        variant of the parent peptide with the amino acid sequence of        SEQ ID NOs: SEQ ID NO: 81 (pep-109) may be a peptide with the        amino acid sequence of SEQ ID NO: 221, 245 or 246.

As mentioned any parent peptide or a variant thereof may be amidated.Therefore, in some embodiments, a variant of a parent peptide isamidated at the C-terminus.

Peptides disclosed herein and variants, derivatives or salts thereof aretypically manufactured synthetically. Thus, in certain embodiments,peptides, variants, derivatives and salts thereof are synthetic. Thepeptides, variants, derivatives and salts may be isolated and/orpurified, e.g. made by the hand of man, such as by peptide synthesis.Typically, the peptides may be combined after synthesis and freeze-driedor dissolved in aqueous solutions, DMSO, glycerol or the like ormixtures thereof. Typically, each peptide of a peptide combination ispresent in equimolar concentrations or substantially equimolar ranges.Typically, the peptides are freeze-dried (lyophilized), such as toprovide them in a storage-stable form and in a form ready to bere-dissolved. The concentration of each of the re-dissolved peptides maybe in a molar concentration in the range of 1 to 1000 μM, for example inthe range of 10 to 800 μM, for example in the range of 20 to 500 μM, forexample in the range of 20 to 300 μM.

Pharmaceutical Compositions

The invention also features a pharmaceutical composition comprising acomposition, e.g. a peptide combination, defined herein. Thepharmaceutical composition may be a vaccine, e.g. a product for use inconducting immunotherapy, including but not limited to a vaccine fortreating an allergic immune response to a house dust mite allergen.

A pharmaceutical composition comprises in addition to the peptidecombination, therapeutically inactive ingredients, such as apharmaceutically acceptable or physiologically acceptable excipient,carrier and/or adjuvants, which are well-known to the person skilled inthe art and may include, but are not limited to, solvents, emulsifiers,wetting agents, plasticizers, solubilizers (e.g. solubility enhancingagents) coloring substances, fillers, preservatives, anti-oxidants,anti-microbial agents, viscosity adjusting agents, buffering agents, pHadjusting agents, isotonicity adjusting agents, mucoadhesive substances,and the like. Examples of formulation strategies are well-known to theperson skilled in the art.

In some embodiments, the peptide may be formulated (e.g. mixed together)with immune-modifying agents like adjuvants. The adjuvant may be anyconventional adjuvant, including but not limited to oxygen-containingmetal salts, e.g. aluminium hydroxide, chitosan, heat-labile enterotoxin(LT), cholera toxin (CT), cholera toxin B subunit (CTB), polymerizedliposomes, mutant toxins, e.g. LTK63 and LTR72, microcapsules,interleukins (e.g. IL-1 BETA, IL-2, IL-7, IL-12, INFGAMMA), GM-CSF, MDFderivatives, CpG oligonucleotides, LPS, MPL, MPL-derivatives,phosphophazenes, Adju-Phos®, glucan, antigen formulation, liposomes,DDE, DHEA, DMPC, DMPG, DOC/Alum Complex, Freund's incomplete adjuvant,ISCOMs®, LT Oral Adjuvant, muramyl dipeptide, monophosphoryl lipid A,muramyl peptide, and phospatidylethanolamine. Additional examples ofadjuvants are described, for example, in “Vaccine Design—the subunit andadjuvant approach” (Edited by Powell, M. F. and Newman, M. J.; 1995,Pharmaceutical Biotechnology (Plenum Press, New York and London, ISBN0-306-44867-X) entitled “Compendium of vaccine adjuvants and excipients”by Powell, M. F. and Newman M.

In some embodiments, the pharmaceutical composition may be formulatedfor parenteral administration, such as formulated for injection, e.g.subcutaneous and/or intradermal injection. Therefore, in someembodiments, the pharmaceutical composition may be a liquid (i.e.formulated as a liquid), including a solution, a suspension, adispersion, and a gelled liquid. For example, a liquid pharmaceuticalcomposition may be formed by dissolving a powder, granulate orlyophilizate of a peptide combination described herein in a suitablesolvent and then administering to a subject. Suitable solvents may beany solvent having physiologically acceptable properties and able todissolve the peptide combination in desired concentrations. A desiredconcentration may depend on the aliquot to be administered (i.e. to beinjected) and the desired single dose. It is emphasized that for thepurposes of injection the aliquot is in the range of about 10 to 500microliters, e.g. 50 to 300 microliters or less and a desired singledose is within range of 1 to 1000 nanomole. Therefore, a suitablesolvent should be able to dissolve any peptide of the combination toachieve a final concentration of about 1 to 1000 μM for each of thepeptides. Thus, in one embodiment, a liquid composition comprises eachof the peptides of the combination in a concentration of 10 to 800 μM,for example 20 to 500 μM or 20 to 300 μM. Typically, the concentrationof each peptide is the same, such as in an equimolar concentration, buteach peptide of the composition may be present in differentconcentrations. Typically, the solvent is an aqueous solution,optionally mixed with other solvents. Thus, a solvent may comprise atleast 60% w/w of water, e.g. at least 65% w/w, 70% w/w, 75% w/w, 80%w/w, 85% w/w, 90% w/w or 95% w/w, 99% w/w of water, such as distilledwater, such as sterile water. In some embodiments, the solvent issterile distilled water, e.g. water for injection. An aqueous solutionmay comprise other solvents than water, for example DMSO(dimethylsulfoxide), glycerol, ethanol, acetonitrile, vegetable orsynthetic oils. The pH of the aqueous phase of the solvent may be in aphysiological acceptable range, typically in the range of 3 to 9, suchas in the range of pH 3 to 8, such as in the range of pH 4 to 8, such asin the range of 5 to 8, such as in the range of 6 to 8. Thus, the liquidformulation may comprise a pH controlling agent or buffering agent (e.g.citrate buffer, phosphate buffer, acetate buffer), optionally the pH maybe adjusted with dilutions of strong base (e.g. sodium hydroxide or thelike) and/or dilutions of strong acids (e.g. hydrochloric acid).

Typically, the liquid formulation is isotonic, and optionally sterile.Therefore, in some embodiments, the formulation comprises saline, suchas isotonic saline. The liquid may contain additional excipients, suchas another solvent, a solubilizing enhancing agent (e.g. polyoxyethylene(20) sorbitan monolaurate (Tween® 20), ionic and non-ionic emulsifiers(e.g. poloxamers (Kolliphor®)), a dispersant, a thickener, apreservative, an anti-microbial agent, and/or an antioxidant.Non-limiting illustrative examples of solvents include water, saline,DMSO, glycerol, ethanol, acetonitrile, vegetable or synthetic oils.

Some peptides are known to be prone to oxidation or being unstable whenexposed to water for a long period. Therefore, to achieve storage stablecompositions, a pharmaceutical composition may be formulated to containonly a limited amount of water or aqueous solution, e.g. containing lessthan 10% w/w of water or aqueous solution, such as less than 9, 8, 7, 6,5, 4, 3, 2, 1, 0.5% w/w of water or aqueous solution. Examples ofpharmaceutical compositions with limited levels of water may includegranulates, powders, for example lyophilizates, i.e. freeze-driedpowders. Typically, the freeze-dried composition may be dissolved beforeuse, for example dissolved in an aqueous, optionally sterile, solution,for example a solution having a pH in the range of 3-9, such as pH inthe range of 3 to 8, such as pH in the range of 4 to 8. A lyophilizatemay contain additional ingredients, e.g. bulking agents andlyoprotectants (e.g. sucrose, lactose, trehalose, mannose, mannitol,sorbitol, glucose, raffinose, glycine, histidine or mixtures thereof),buffering agents (e.g. sodium citrate, sodium phosphate, disodiumphosphate, sodium hydroxide, Tris base, Tris acetate, Tris HCl ormixtures thereof), antioxidants, antimicrobial agents, solubilizers(e.g. polyoxyethylene (20) sorbitan monolaurate (Tween® 20)).

A freeze-dried composition may also be formulated into a solid dosageform that is administered for example by the oral route such as by oralmucosa. Thus, in some embodiments, the pharmaceutical composition may beformulated for oral administration, for example for sublingualadministration. Therefore, the pharmaceutical composition may be a soliddosage form, such as a freeze-dried solid dosage form, typically atablet, a capsule or sachet, which optionally may be formulated for fastdisintegration.

Pharmaceutical formulations and delivery systems appropriate for thecompositions, methods and uses of the invention are known in the art(see, e.g., Remington: The Science and Practice of Pharmacy (2003) 20thed., Mack Publishing Co., Easton, Pa.; Remington's PharmaceuticalSciences (1990) 18th ed., Mack Publishing Co., Easton, Pa.; The MerckIndex (1996) 12th ed., Merck Publishing Group, Whitehouse, N.J.;Pharmaceutical Principles of Solid Dosage Forms (1993), TechnonicPublishing Co., Inc., Lancaster, Pa.; Ansel ad Soklosa, PharmaceuticalCalculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore,Md.; and Poznansky et al., Drug Delivery Systems (1980), R. L. Juliano,ed., Oxford, N.Y., pp. 253-315).

As mentioned, pharmaceutical compositions can be formulated to becompatible with a particular route of administration, such as byintradermal or by sublingual administration. Thus, pharmaceuticalcompositions may include carriers, diluents, or excipients suitable foradministration by various routes. Exemplary routes of administration forcontact or in vivo delivery for which a composition can optionally beformulated include inhalation, intranasal, oral, buccal, sublingual,subcutaneous, intradermal, epicutaneous, rectal, transdermal, orintralymphatic.

For oral, buccal or sublingual administration, a composition may takethe form of, for example, tablets or capsules, optionally formulated asfast-integrating tablets/capsules or slow-release tablets/capsules. Insome embodiments, the tablet is freeze-dried, optionally afast-disintegrating tablet or capsule suitable for being administeredunder the tongue.

The pharmaceutical composition may also be formulated into a “unitdosage form”, which used herein refers to physically discrete units,wherein each unit contains a predetermined quantity of a peptide orpeptide combination, optionally in association with a pharmaceuticalcarrier (excipient, diluent, vehicle or filling agent) which, whenadministered in one or more doses, may produce a desired effect. Unitdosage forms also include, for example, ampules and vials, which mayinclude a composition in a freeze-dried or lyophilized state (alyophilizate) or a sterile liquid carrier, for example that can be addedprior to administration or delivery in vivo. Unit dosage formsadditionally include, for example, ampules and vials with liquidcompositions disposed therein.

Peptides may be prone to degradation when exposed to oxygen, for examplewhen exposed to air or solvents containing air. Therefore, in someembodiments, the pharmaceutical composition comprises an inert gas, e.g.argon or nitrogen.

Another aspect of the invention relates to a kit comprising acompartment and instructions, wherein the compartment comprises apharmaceutical composition as described herein and wherein theinstructions are for use in treating allergy to dust mites, such ashouse dust mites. A kit may further comprise packaging materialcomprising corrugated fiber, glass, plastic, foil, ampules, vials,blister pack, preloaded syringes or tubes, optionally that maintainsterility of the components. A kit may further comprise labels orinserts comprising printed matter or computer readable medium optionallyincluding identifying components, dose amounts, clinical pharmacologyand instructions for the clinician or for a subject using one or more ofthe kit components, prophylactic or therapeutic benefits, adverse sideeffects or manufacturer information.

In one embodiment, the kit additionally comprises a container comprisinga solvent for dissolving the composition before use. Examples ofsuitable solvents are described supra.

Optionally, the kit may also comprise a device for use in parenteralinjection, e.g. for injecting the composition (e.g. dissolvedcomposition) to a subcutaneous or intradermal tissue. A device may beany suitable device for that purpose, such as a needle or microneedleadapted for intradermal or subcutaneous delivery of the composition. Forexample, the device may be a microneedle or a device comprising aplurality of microneedles designed for intradermal delivery of liquids,e.g. as described in international patent applications WO14064543 A1,WO05049107 A2, WO06054280 A2, WO07066341 A3 and WO14188429 A1.

Therapy

Compositions (e.g. peptide combinations) described herein may be usedfor the treatment of an immune response or allergy to a dust mite, suchas a house dust mite, in a subject in need thereof. Allergy to a dustmite may be clinically presented in the subject as atopic dermatitis,urticaria, contact dermatitis, allergic conjunctivitis, allergicrhinitis, allergic asthma, anaphylaxis, and/or hay fever. Therefore, insome aspects of the present invention, the method comprises decreasing,reducing, suppressing or inhibiting atopic dermatitis, urticaria,contact dermatitis, allergic conjunctivitis, allergic rhinitis, allergicasthma, anaphylaxis, and/or hay fever.

The phrase “treatment of an immune response” or “treating an immuneresponse” may encompass preventing, relieving, alleviating, reducing,inhibiting, decreasing, or suppressing an immune response, for examplean allergic immune response, such as an immune response against a miteallergen (e.g. house dust mite allergen). The treatment of an immuneresponse may also include the decrease, inhibition, suppression orreduction of a T cell response, which may include but is not limited toa Th2 cell response or a memory T cell response. Furthermore, thetreatment of an immune response described herein may also compriseinducing, promoting, increasing or enhancing proliferation of regulatoryT cells while optionally decreasing, reducing, inhibiting, suppressingor reducing production of pro-inflammatory lymphokines/cytokines.

Therefore, in some aspects, the invention relates to a method forrelieving an immune response to an allergen of a dust mite (e.g. a housedust mite) in a subject in need thereof, comprising administering tosaid subject a therapeutically effective amount of a compositiondescribed herein (e.g. a peptide combination described herein).

In other aspects, the administration of a composition described hereinmay induce immunological tolerance against the allergen(s) of said dustmite.

Thus, compositions disclosed herein may produce a therapeutic orbeneficial effect, which optionally may be objectively or subjectivelymeasurable. A therapeutic or beneficial effect can but need not becomplete ablation of all or any immune response, or one or more symptomscaused by or associated with an allergen. Thus, a satisfactory clinicalresult is achieved when there is an incremental improvement or a partialreduction in an immune response or one or more symptoms caused by orassociated with an allergen, or there is an inhibition, decrease,reduction, suppression, prevention, limit or control of worsening orprogression of an immune response or one or more symptoms caused by orassociated with an allergen over a short or long duration (hours, days,weeks, months, etc.).

Therefore, in still other aspects, the subject's administration of atherapeutically effective amount of a composition described herein mayrelieve one or more symptoms of the immune response. For example, themethod may comprise relieving one or more symptoms associated withallergic rhinitis, allergic conjunctivitis, allergic asthma and/orallergic eczema (e.g. atopic dermatitis).

In some embodiments, the one or more symptoms may be associated withallergic rhinitis. For example, the method may comprise reducing one ormore of the following symptoms: intensity of itchy nose; number ofsneezes within a given period (e.g. daily, weekly, monthly); intensityof blocked nose (e.g. congestion); amount of nasal secretions;eosinophilic count in nasal secretions; specific IgE antibody level(titer) in nasal secretions or in serum; and basophil histamine releaseof blood.

In other embodiments, the one or more symptoms may be associated withallergic conjunctivitis. For example, the method may comprise reducingone or more of the following symptoms: intensity of itchy eyes, rednessin the white of the eyes and/or watery eyes; eosinophilic count inconjunctival tissue scrapings; specific IgE antibody level (titer) inconjunctival tissue scrapings or in serum; and basophil histaminerelease in blood.

In some embodiments, the one or more symptoms may be associated withallergic asthma. For example, the method may comprise reducing one ormore of the following symptoms: number of or frequency of asthmaexacerbations (optionally that require hospitalization), intensityand/or number of coughs within a given period (e.g. daily, weekly,monthly); intensity of wheezes; intensity of shortness of breath orcongestion (e.g. improvement of being short of breath); reducing ForcedExpiratory Volume (FEV1); reducing specific IgE antibody level (titer)in lung fluid or in serum and basophil histamine release in blood; orthe method may comprise improving lung function.

In some embodiments, the one or more symptoms may be symptoms associatedwith atopic dermatitis. For example, the method may comprise reducingone or more of the following symptoms: itch intensity of the skin;eczema score, and number of (peripheral) blood eosinophils.

A therapeutic or beneficial effect also includes reducing or eliminatingthe need, dosage frequency or amount of a second therapeutic method ortherapeutically active drug (e.g. anti-inflammatory, decongestants oranti-allergic agent) used for treating a subject having an immuneresponse or one or more symptoms caused by or associated with anallergen. For example, administration of a peptide combination describedherein may reduce the amount of an adjunct therapy administered to asubject, such as reducing the subject's need for concomitant treatmentwith fast or long-acting β2-agonists, leukotriene modifiers,theophylline corticosteroids or H1 antihistamines (e.g. inhaled or oral)to reduce, relieve, or suppress one or more symptoms of the immuneresponse.

As used herein, the term “immune response” includes T cell (cellular)mediated and/or B cell (humoral) mediated immune responses, or bothcellular and humoral responses. In particular, the term “immuneresponse” may include an IgE-mediated immune response (i.e. an allergicimmune response). Exemplary immune responses include T cell responses,such as Th2 responses resulting in cytokine production and/or cellularcytotoxicity. In addition, the term “immune response” includes responsesthat are indirectly affected by T cell activation, e.g., antibodyproduction (humoral responses) and activation of cytokine responsivecells, e.g., eosinophils, macrophages. Immune cells involved in theimmune response include lymphocytes, such as T cells (CD4+, CD8+, Th1and Th2 cells, memory T cells) and B cells; antigen presenting cells(e.g., professional antigen presenting cells such as dendritic cells,macrophages, B lymphocytes, Langerhans cells, and non-professionalantigen presenting cells such as keratinocytes, endothelial cells,astrocytes, fibroblasts, oligodendrocytes); natural killer (NK) cells;and myeloid cells, such as macrophages, eosinophils, mast cells,basophils, and granulocytes. A particular immune response is productionof immunoglobulin (Ig) isotypes antibodies or decreasing IgE antibodies.

Therefore, in some embodiments, the method comprises inducing orincreasing an IgG antibody (e.g. specific IgG) response in a subject toan allergen of a dust mite. In still some embodiments, the methodcomprises decreasing an IgE antibody (e.g. specific IgE) response in asubject to an allergen of a dust mite. In still some embodiments, themethod comprises decreasing a T cell response in a subject to anallergen of a dust mite, for example decreasing the production of Th-2associated cytokines, like IL-5, IL-4, IL-13 in response to saidallergen.

The term “modulating an immune response” or “modulate an immuneresponse” may include to stimulate, induce, promote, increase or enhancean immune response, e.g. a T cell regulatory response, or may includeinhibiting, decreasing, suppressing or reducing a T cell response, whichmay include, but is not limited to a Th2 cell response.

Without being limited to a particular mechanism of action, a peptidecombination of the invention may modulate, such as suppress a T cell oran antibody response. For example, a T cell response and/or antibodyresponse triggered by a dust mite allergen (e.g. house dust miteallergen) may be suppressed or inhibited by a peptide combinationdescribed herein. Typically, a T cell response is associated with acytokine response, e.g. IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10,IL-12, IL-13, IL-17, IL-22, IL-31 or IFN-g response. In particularembodiments, the T cell response against a dust mite allergen may resultin decreased production in a subset of the cytokines, for examplecytokines associated with a Th2-mediated response (e.g. IL-4, IL-5and/or IL-13), and may optionally also result in increased production ofcytokines associated with a Tregs (e.g. IL-10).

As mentioned, peptide combinations described herein may provide abeneficial effect on an immune response against a dust mite allergen.Exemplary dust mites are the house dust mites of the genusDermatophagoides that include, but are not limited to, the speciesDermatophagoides farinae (American house dust mite) and Dermatophagoidespteronyssinus (European house dust mite); the house dust mites of thegenus Euroglyphus that include, but are not limited to, the speciesEuroglyphus maynei; and the house dust mites of the genus Blomia thatinclude, but are not limited to, the species Blomia tropicalis. The twolatter house dust mite species are mainly found in subtropical/tropicalregions around the world and both species are known to compriseallergens that cross-react with antibodies produced in response toallergens of Dermatophagoides mites.

A dust mite allergen may be any allergen detected in a house dust mite(e.g. of the genus Dermatophagoides, Euroglyphus and/or Blomia).Exemplary dust mite allergens of Dermatophagoides farinae are: Der f 1,Der f 2, Der f 3, Der f 6, Der f 7, Der f 10, Der f 11, Der f 13, Der f14, Der f 15, Der f 16, Der f 17, Der f 18 and Der f 22; exemplary dustmite allergens of Dermatophagoides pteronyssinus are: Der p 1, Der p 2,Der p 3, Der p 4, Der p 5, Der p 6, Der p 7, Der p 8, Der p 9, Der p 10,Der p 11, Der p 14, Der p 20, Der p 21 and Der p 23; exemplary dust miteallergens of Blomia tropicalis are: Blo t 1, Blo t 2, Blo t 3, Blo t 4,Blo t 5, Blo t 6, Blo t 10, Blo t 11, Blo t 12, Blo t 13, Blo t 19 andBlo t 21; exemplary dust mite allergens of Euroglyphus maynei are: Eur m1, Eur m 2, Eur m 3, Eur m 4 and Eur m 14.

Typically, the dust mite allergen is a major dust mite allergen, forexample a house dust mite Group 1 allergen, like Der p 1 and Der f 1,optionally Blo t 1 and Eur m 1, or a house dust mite Group 2 allergenlike Der p 2 and Der f 2, optionally Blo t 2 and Eur m 2.

Typically, the treatment comprises repeated administration of thecomposition with weekly, bi-weekly, monthly or quarterly intervals.Thus, in a particular embodiment, the treatment comprises immunotherapywith single doses repeatedly administered until a persistent effect isachieved. Immunotherapy is thought to produce immunological tolerance inthe subject undergoing therapy. Thus, in still other embodiments, thecompositions, such as peptide combinations, may be used to induceimmunological tolerance in a subject in need thereof.

As used herein, the term “immunological tolerance” refers to a) adecreased or reduced level of a specific immunological response (thoughtto be mediated at least in part by antigen-specific effector Tlymphocytes, B lymphocytes, antibodies, or a combination thereof); b) adelay in the onset or progression of a specific immunological response;or c) a reduced risk of the onset or progression of a specificimmunological response (e.g. to a house dust mite allergen). Anincrease, improvement, enhancement or induction of “tolerance” may referto a decrease, reduction, inhibition, suppression, or limiting orcontrolling or clearing of specific immunological reactivity to anallergen as compared to reactivity to the allergen in a previousexposure to the same allergen. Thus, in certain embodiments, the methodcomprises inducing immunological tolerance in a subject to an allergen(e.g. house dust mite allergen) to suppress an allergic immune responseto the allergen. Immunological tolerance in a subject to an allergen canalso be reflected by reducing the occurrence, frequency, severity,progression, or duration of an allergic response of the subject to theallergen. Induction of immune tolerance (also referred to asdesensitization), and the relative amount of immune tolerance, can bemeasured by methods disclosed herein or known to the skilled artisan.For example, induction of immune tolerance can be measured by themodulated lymphokine and/or cytokine level in a subject or animal beforeversus after administering a peptide combination described herein forthe first time. A modulated cytokine level can be an increase of acytokine level, for instance an increase of a lymphokine and/or cytokinelevel of at least 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 20, 50 times or morerelative to before administering the peptide combination for the firsttime. Alternatively, modulation can be a decrease of the level of aparticular cytokine level, for instance a decrease of the lymphokineand/or cytokine level of at least 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 20, 50times or more relative to before administering the peptide combinationfor the first time. The lymphokines/cytokines chosen to measure can befrom any relevant lymphokines/cytokines, such as IL-2, IL-5, IL-4, IL-6,IL-10, IL-12, IL-13, IL-17, TNF-alfa, IFN-gamma, TGF-beta, MCP-1, RANK-Land Flt3L. Accordingly, the term “inducing immunological tolerance” mayinclude eliciting, stimulating, promoting, increasing or enhancingimmunological tolerance. Immunological tolerance may involve modulationof T cell activity, including but not limited to CD4+ T cells, CD8+ Tcells, Th1 cells, Th2 cells and regulatory T cells (Tregs), and memory Tcells, including inflammatory lymphokines/cytokines produced by T cells.

A peptide combination is typically administered by injection, such as bysubcutaneous or intradermal administration, but may also include otherroutes of administration, such as epicutaneous, rectal, sublingual,oral, buccal, intranasal, respiratory and intralymphatic route ofadministration.

The peptide combination may be administered to any subject in needthereof, for example a human, a pet such as a dog or a cat, a domesticanimal such as a horse, or a laboratory animal like a mouse, a guineapig or a rabbit. The subject may be sensitized to an allergen of a dustmite (e.g. having specific IgE antibodies against an allergen of a dustmite and/or having a T cell response against an allergen of a dustmite). Therefore, a subject in need thereof may produce specific IgEantibodies or a T cell response against house dust mite allergens Der p1, Der p 2, Der f 1 and/or Der f 2, and optionally other dust miteallergens as described supra including an aqueous extract of a housedust mite or a house dust mite faeces.

The peptide combination may be administered in clinically relevantdoses, such as therapeutically sufficient doses. For example, a singledose of each peptide of the composition may be in the range of 1 to 1000nanomole, for example 1 to 500 nanomole, for example 1 to 250 nanomole,for example 5 to 250 nanomole, which single dose may be repeated oncedaily, weekly, biweekly or monthly or quarterly. Typically, the peptidecombination is a liquid administered in a volume of about 50 to 150microliter, such as by intradermal administration.

The compositions described herein may be dosed in a dosage regimenusually applied in the field of allergy immunotherapy, such peptideallergy immunotherapy. For example, compositions may be administered asa single dose (e.g. one injection) with daily, weekly, bi-weekly,monthly or quarterly intervals over a period of at least 2-6 months oreven longer until a more persistent effect is achieved. The term“persistent effect” means that one or more clinically relevant symptomsof the immune response is reduced in the subject when exposed to anallergen of a house dust mite compared to before the subject isadministered the first dose. A persistent effect may be evaluated atleast two months after the subject has stopped treatment, such as afterat least three, four, five, six, nine or twelve months. It is alsoenvisaged that the treatment is initiated by an up-dosing phase with thepeptide combination being administered in increasing doses within oneday or with daily, weekly or bi-weekly intervals until the targetmaintenance dose is achieved.

The subject administered a peptide combination described herein mayoptionally also be administered another therapeutic agent used fortreating an immune response against a dust mite allergen. However, insome embodiments, the subject is not co-administered the peptidecombination of another immunogen, e.g. an allergen extract or allergen,e.g. allergen extract or allergen of a house dust mite. Thus, in certainembodiments, a composition described herein may not comprise an allergenextract.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described herein.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims. The invention is further exemplified byway of the following non-limited examples.

A still other aspect of the invention relates to an in vitro method ofdetermining whether T cells of a subject in need of treatment recognizea composition as described herein, comprising contacting T cellsobtained from the subject with said composition or a single peptidethereof and detecting whether the T cells are stimulated by saidcomposition or single peptide. The in vitro method may be used todetermine whether the subject has, or is at risk of developing, anallergy to a dust mite allergen.

The invention is further described by the following embodiments 1 to119:

Embodiment 1

A composition comprising at least three peptides, wherein thecomposition comprises peptides selected from at least three of thefollowing peptide groups:

-   group 26.: a parent peptide with the amino acid sequence SEQ ID NOs:    82 (pep-110), 269 (pep-125), 70 (pep-099) or 253 (pep-012); or a    variant thereof;-   group 24.: a parent peptide with the amino acid sequence SEQ ID NOs:    271 (pep-131), 67 (pep-096), 79 (pep-108), 256 (pep-031) or 270    (pep-126); or a variant thereof;-   group 14.: a parent peptide with the amino acid sequence SEQ ID NOs:    268 (pep-130) or 22 (pep-054); or a variant thereof;-   group 1.: a parent peptide with the amino acid sequence SEQ ID NO:    90 or a variant thereof;-   group 2.: a parent peptide with the amino acid sequence SEQ ID NO:    280 or a variant thereof;-   group 3.: a parent peptide with the amino acid sequence SEQ ID NO: 9    (pep-041) or a variant thereof;-   group 4.: a parent peptide with the amino acid sequence SEQ ID NO:    10 (pep-042) or a variant thereof;-   group 5.: a parent peptide with the amino acid sequence SEQ ID NO:    11 (pep-043) or a variant thereof;-   group 6.: a parent peptide with the amino acid sequence SEQ ID NO:    12 (pep-044) or a variant thereof;-   group 7.: a parent peptide with the amino acid sequence SEQ ID NOs:    42 (pep-072) or 249 (pep-022); or a variant thereof;-   group 8.: a parent peptide with the amino acid sequence SEQ ID NO:    15 (pep-047) or a variant thereof;-   group 9.: a parent peptide with the amino acid sequence SEQ ID NOs:    266 (pep-123), 255 (pep-025), 46 (pep-075) or 17 (pep-049); or a    variant thereof;-   group 10.: a parent peptide with the amino acid sequence SEQ ID NOs:    18 (pep-050), 258 (pep-122) or 267 (pep-124); or a variant thereof;-   group 11.: a parent peptide with the amino acid sequence SEQ ID NO:    120; or a variant thereof;-   group 12.: a parent peptide with the amino acid sequence SEQ ID NOs:    20 (pep-052) or 49 (pep-078); or a variant thereof;-   group 13.: a parent peptide with the amino acid sequence SEQ ID NO:    21 (pep-053) or a variant thereof;-   group 15.: a parent peptide with the amino acid sequence SEQ ID NOs:    52 (pep-081) or 23 (pep-055, 272); or a variant thereof;-   group 16.: a parent peptide with the amino acid sequence SEQ ID NO:    26 (pep-058) or a variant thereof;-   group 17.: a parent peptide with the amino acid sequence SEQ ID NOs:    29 (pep-061), 58 (pep-087), 251 (pep-10) or 252 (pep-011); or a    variant thereof;-   group 18.: a parent peptide with the amino acid sequence SEQ ID NO:    71 (pep-100) or a variant thereof;-   group 19.: a parent peptide with the amino acid sequence SEQ ID NO:    72 (pep-101) or a variant thereof;-   group 20.: a parent peptide with the amino acid sequence SEQ ID NOs:    61 (pep-090), 73 (pep-102) or 276; or a variant thereof;-   group 21.: a parent peptide with the amino acid sequence SEQ ID NO:    62 (pep-091) or a variant thereof;-   group 22.: a parent peptide with the amino acid sequence SEQ ID NOs:    63 (pep-092) or 278; or a variant thereof;-   group 23.: a parent peptide with the amino acid sequence SEQ ID NO:    77 (pep-106) or a variant thereof; and group 25.: a parent peptide    with the amino acid sequence SEQ ID NO: 81 (pep-109) or a variant    thereof.

Embodiment 2

The composition according to embodiment 1, wherein at least one peptideis selected from any one of the peptide groups 1-17.

Embodiment 3

The composition according to any one of the preceding embodiments,wherein at least one peptide is selected from any one of the peptidegroups 18-26.

Embodiment 4

The composition according to any one of the preceding embodiments,wherein the at least three peptides are selected from three of thepeptide groups 4, 5, 6, 9, 10, 13, 14, 15, 16, 17, 20, 21, 24, 25 and26.

Embodiment 5

The composition according to any one of the preceding embodiments,wherein the at least three peptides are selected from three of thepeptide groups 9, 10, 13, 14, 16, 20, 21, 24, 25 and 26.

Embodiment 6

The composition according to any one of the preceding embodiments,wherein the composition comprises an additional peptide selected fromany one of the peptide groups 1-26 from which there is no other peptidein the composition.

Embodiment 7

The composition according to any one of the preceding embodiments,wherein the composition does not comprise a peptide from peptide group 7and/or peptide group 20.

Embodiment 8

The composition according to embodiment 7, wherein the composition doesnot comprise as three of the peptides, peptides from each of the peptidegroups 7, 20 and 17.

Embodiment 9

The composition according to any one of the preceding embodiments,wherein the composition comprises as one of the peptides a peptide frompeptide group 26 (e.g. parent peptide pep-110 or a variant thereof).

Embodiment 10

The composition according to embodiment 9, wherein the compositioncomprises as one of the peptides a peptide selected from any one of thepeptide groups 1-17.

Embodiment 11

The composition according to any one of the preceding embodiments,wherein the composition comprises as one of the peptides a peptide frompeptide group 26 (e.g. parent peptide pep-110) and comprises as one ofthe peptides a peptide selected from any one of the peptide groups 24,17, 9 or 16.

Embodiment 12

The composition according to embodiment 11, wherein the compositioncomprises as two of the peptides, a peptide from peptide group 26 (e.g.parent peptide pep-110) and a peptide from peptide group 24 (e.g. parentpeptide pep-131).

Embodiment 13

The composition according to embodiment 12, wherein the third peptide isselected from any one of the peptide groups 4, 5, 6, 9, 10, 13, 14, 15,16 and 17.

Embodiment 14

The composition according to any one of embodiments 12 and 13, whereinthe third peptide is from peptide group 14.

Embodiment 15

The composition according embodiment 14, wherein an additional peptideis selected from any one of the peptide groups 1-13, 15-23 and 25.

Embodiment 16

The composition according to embodiment 14, wherein an additionalpeptide is selected from any one of the peptide groups 9, 16 and 21.

Embodiment 17

The composition according to any one of embodiments 12 to 16, comprisingfive peptides, wherein the composition comprises peptides from each ofthe five peptide groups 26, 24, 14, 9 and 16.

Embodiment 18

The composition according to embodiment 17, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof.

Embodiment 19

The composition according to embodiment 17, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof.

Embodiment 20

The composition according to any one of embodiments 12 to 16, comprisingfive peptides, wherein the composition comprises peptides from each ofthe five peptide groups 26, 24, 14, 9 and 21.

Embodiment 21

The composition according to embodiment 20, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 22

The composition according to embodiment 20, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 23

The composition according to any one of embodiments 12 to 16, comprisingfive peptides, wherein the composition comprises peptides from each ofthe five peptide groups 26, 24, 14, 16 and 21.

Embodiment 24

The composition according to embodiment 23, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 25

The composition according to any one of embodiments 12 and 13, whereinthe third peptide is from peptide group 9 or from peptide group 21.

Embodiment 26

The composition according to embodiment 25, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 24, 21, 9 and 13.

Embodiment 27

The composition according to embodiment 26, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 271(pep-131) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 21 (pep-053)or a variant thereof.

Embodiment 28

The composition according to any one of embodiments 12 and 13, whereinthe third peptide is from peptide group 17.

Embodiment 29

The composition according embodiment 28, comprising an additionalpeptide selected from any one of the peptide groups 1-16, 18-23 and 25.

Embodiment 30

The composition according to any one of embodiments 28 and 29, whereinan additional peptide is selected from any one or both of the peptidegroups 7 and 10.

Embodiment 31

The composition according to embodiment 30, comprising five peptides,wherein the composition comprises a peptide from each of the fivepeptide groups 26, 24, 17, 7 and 10.

Embodiment 32

The composition according to embodiment 31, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 256(pep-031) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 252(pep-011) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 254(pep-022) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof.

Embodiment 33

The composition according to embodiment 31, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 256(pep-031) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 251(pep-010) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 254(pep-022) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof.

Embodiment 34

The composition according to embodiment 30, comprising five peptides,wherein the composition comprises peptides from each of the four peptidegroups 26, 24, 17 and 10; and a peptide with the amino acid sequence SEQID NO: 117 (pep-p4) or a variant thereof.

Embodiment 35

The composition according to embodiment 34, comprising

a) a parent peptide with the amino acid sequence SEQ ID NO: 253(pep-012) or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 256(pep-031) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 252(pep-011) or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 258(pep-122) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 117 or avariant thereof.

Embodiment 36

The composition according to embodiment 11, wherein the compositioncomprises as two of the peptides, a peptide from peptide group 26 (e.g.parent peptide 110) and a peptide from peptide group 17. (e.g. parentpeptide pep-058, pep-010, pep-011 or pep-061).

Embodiment 37

The composition according to embodiment 36, comprising three peptides,wherein the composition comprises peptides from each of the threepeptide groups 26, 17 and 6.

Embodiment 38

The composition according to embodiment 37, comprising

a) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 251(pep-010) or a variant thereof; and

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof.

Embodiment 39

The composition according to embodiment 11, wherein the compositioncomprises as two of the peptides, a peptide from peptide group 26 (e.g.parent peptide 110) and a peptide from peptide group 9. (e.g. parentpeptide pep-123, pep-025, pep-075 or pep-049).

Embodiment 40

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 6, 16 and 19.

Embodiment 41

The composition according to embodiment 40, comprising

a) a parent peptide with the amino acid sequence SEQ ID NO: 70 (pep-099)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 60 (pep-089)or a variant thereof.

Embodiment 42

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 6, 18 and 20.

Embodiment 43

The composition according to embodiment 42, comprising

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 71 (pep-100)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 73 (pep-102)or a variant thereof.

Embodiment 44

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 6, 12 and 21.

Embodiment 45

The composition according to embodiment 44, comprising

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 17(pep-049)) or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 12 (pep-044)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 20 (pep-052)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 46

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 16, 3 and 25.

Embodiment 47

The composition according to embodiment 46, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 81 (pep-109)or a variant thereof.

Embodiment 48

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 16, 14 and 25.

Embodiment 49

The composition according to embodiment 48, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 22 (pep-054)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 81 (pep-109)or a variant thereof.

Embodiment 50

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 16, 3 and 21.

Embodiment 51

The composition according to embodiment 50, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 52

The composition according to embodiment 39, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 9, 16, 14 and 21.

Embodiment 53

The composition according to embodiment 52, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 46 (pep-075)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 54

The composition according to embodiment 11, wherein the compositioncomprises as two of the peptides, a peptide from peptide group 26 (e.g.parent peptide pep-110 or a variant thereof) and a peptide from peptidegroup 16 (e.g. parent peptide pep-058 or a variant thereof).

Embodiment 55

The composition according to embodiment 54, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 16, 3, 15 and 25.

Embodiment 56

The composition according to embodiment 55, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 9 (pep-041)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 52 (pep-081)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 81 (pep-109)or a variant thereof.

Embodiment 57

The composition according to embodiment 54, comprising five peptides,wherein the composition comprises peptides from each of the five peptidegroups 26, 16, 14, 15 and 21.

Embodiment 58

The composition according to embodiment 57, wherein the compositioncomprises

a) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof;

b) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof;

c) a parent peptide with the amino acid sequence SEQ ID NO: 22 (pep-054)or a variant thereof;

d) a parent peptide with the amino acid sequence SEQ ID NO: 52 (pep-081)or a variant thereof; and

e) a parent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091)or a variant thereof.

Embodiment 59

The composition according to any one of the preceding embodiments,wherein the peptides in the composition are all selected from differentpeptide groups, for example a maximum of 3 peptides selected from eachof 3 different peptide groups, for example a maximum of 4 peptidesselected from each of 4 different peptide groups, for example a maximumof 5 peptides selected from each of 5 different peptide groups, forexample a maximum of 6 peptides selected from each of 6 differentpeptide groups, or for example a maximum of 7 peptides selected fromeach of 7 different peptide groups.

Embodiment 60

The composition according to any one of the preceding embodiments,wherein the variant is a peptide comprising one or more additional aminoacids than the parent peptide and comprises up to 30 amino acid residuesin length, optionally wherein the variant peptide comprises an aminoacid sequence having at least 80% identity over at least 14 contiguousamino acids of the parent peptide.

Embodiment 61

The composition according to any one of the preceding embodiments,wherein the variant is a peptide comprising fewer amino acids than theparent peptide and wherein the amino acid sequence has at least 80%identity over at least 14 contiguous amino acids of the parent peptide.

Embodiment 62

The composition according to any one of embodiments 60 and 61, whereinthe variant consists of 14 to 30 amino acid residues and comprises anamino acid sequence having at least 80% sequence identity over at least15 contiguous amino acids of the parent peptide.

Embodiment 63

The composition according to any one of embodiments 60 and 61, whereinthe variant consists of 15-30 amino acids residues and comprises anamino acid sequence having at least 80% sequence identity over at least15 contiguous amino acids of the parent peptide.

Embodiment 64

The composition according to any one of embodiments 60 and 61, whereinthe variant consists of 15-25 amino acids residues and comprises anamino acid sequence having at least 80% sequence identity over at least15 contiguous amino acids of the parent peptide.

Embodiment 65

The composition according to any one of the preceding embodiments,wherein the variant comprises one or more (e.g. 1, 2, 3, or 4) arginineresidue(s) (R), one or more lysine residue(s) (K), one or more glutamicresidues (E), and/or one or more aspartic acid residues (D) added to theN- or C-terminus of the parent peptide or to a fragment of the parentpeptide consisting of at least 14 contiguous amino acids of the parentpeptide.

Embodiment 66

The composition according to any one of the preceding embodiments,wherein the variant comprises one or more additional amino acid residuesadded at the N- and/or C-terminal ends of the parent peptide, whereinthe one or more additional amino acid residues are the same amino acidor amino acid sequence flanking the N- and/or C-terminal ends of theparent peptide when it is aligned with the wild type amino acid sequenceit is present in, based upon or derived from or is aligned with anotherisoform of the same wild type amino acid sequence.

Embodiment 67

The composition according to any one of the preceding embodiments,wherein the variant comprises a deletion of a hydrophobic residue up tothree amino acids from the N- or C-terminus of the parent peptide;and/or deletion of any two consecutive amino acids comprising thesequence Asp-Gly up to four amino acids from the N- or C-terminus of theparent peptide.

Embodiment 68

The composition according to any one of the preceding embodiments,wherein a peptide of the composition including a variant thereofcontains at least one T cell epitope, optionally a Th-2 cell epitope.

Embodiment 69

The composition according to any one of the preceding embodiments,wherein the variant binds to at least 70% of the group of HLA Class IIalleles that the parent peptide binds to.

Embodiment 70

The composition according to any one of the preceding embodiments,wherein the parent peptide or the variant thereof is derivatized.

Embodiment 71

The composition according to embodiment 70, wherein the parent peptideor the variant thereof is amidated at the C-terminal end.

Embodiment 72

The composition according to embodiment 70, wherein the derivativecomprises (a) N-terminal acetylation; (b) C-terminal amidation (c) oneor more hydrogens on the side chain amines of arginine and/or lysinereplaced with a methylene group; (d) glycosylation and/or (e)phosphorylation.

Embodiment 73

The composition according to any one of the preceding embodiments,wherein the parent peptide or the variant thereof, or a derivative ofthe parent peptide or variant thereof is a salt.

Embodiment 74

The composition according to embodiment 73, wherein the salt is anacetate salt.

Embodiment 75

The composition according to any one of the preceding embodiments,wherein the peptides are synthetically made.

Embodiment 76

The composition according to any one of the preceding embodiments,wherein the peptides are freeze-dried.

Embodiment 77

The composition according to any one of the preceding embodiments,wherein each peptide in the composition is present in equimolarconcentrations or in substantially equimolar concentrations.

Embodiment 78

The composition according to any one of the preceding embodiments,wherein each peptide in the composition is present in a molarconcentration of 1 to 1000 μM.

Embodiment 79

The composition according to any one of embodiments 1 to 78, wherein thecomposition is a pharmaceutical composition.

Embodiment 80

The pharmaceutical composition according to embodiment 79, furthercomprising a pharmaceutically acceptable carrier, excipient and/oradjuvant, optionally sterile.

Embodiment 81

The pharmaceutical composition according to any one of embodiments 79and 80 formulated as a vaccine for parenteral administration.

Embodiment 82

The pharmaceutical composition according to any one of embodiments 79 to81, wherein the pharmaceutical composition is a powder.

Embodiment 83

The pharmaceutical composition according to any one of embodiments 79 to82, wherein the composition is formulated to be re-dissolved before use

Embodiment 84

The pharmaceutical composition according to any one of embodiments 79 to83, wherein the composition is isotonic.

Embodiment 85

A kit comprising a compartment and instructions, wherein the compartmentcomprises the composition according to any one of embodiments 1 to 84and wherein the instructions are for use in treating allergy to dustmites, such as house dust mites.

Embodiment 86

The kit according to embodiment 85, wherein the kit further comprisespackaging material comprising corrugated fiber, glass, plastic, foil,ampules, vials, blister pack, preloaded syringes or tubes, optionallythat maintains sterility of the components.

Embodiment 87

The kit according to any one of embodiments 85 to 86, wherein the kitfurther comprises labels or inserts comprising printed matter orcomputer readable medium optionally including identifying components,dose amounts, clinical pharmacology, instructions for the clinician orfor a subject using one or more of the kit components, prophylactic ortherapeutic benefits, adverse side effects or manufacturer information.

Embodiment 88

A method for relieving or reducing (e.g. treating) an immune responsetriggered by an allergen of a dust mite (e.g. house dust mite) in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the composition according to any oneof embodiments 1 to 84.

Embodiment 89

A method for relieving one or more symptoms of an immune responsetriggered by an allergen of a dust mite (e.g. house dust mite) in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of the composition according to any oneof embodiments 1 to 84.

Embodiment 90

A method for inducing (developing) immunological tolerance against anallergen of a dust mite (e.g. house dust mite), comprising administeringto a subject a therapeutically effective amount of the compositionaccording to any one of embodiments 1 to 84.

Embodiment 91

The method according to any one of embodiments 88 to 90, wherein themethod comprises relieving one or more symptom(s) associated withallergic rhinitis, allergic conjunctivitis, allergic asthma and/orallergic eczema (e.g. atopic dermatitis).

Embodiment 92

The method according to embodiment 91, wherein the one or moresymptom(s) are symptoms associated with allergic rhinitis.

Embodiment 93

The method according to embodiment 92, wherein the method comprisesreducing the intensity of itchy nose; reducing the number of sneezeswithin a given period (e.g. daily, weekly, monthly); reducing theintensity of blocked nose (congestion); reducing the amount of nasalfluid; reducing the eosinophilic count in nasal fluid; reducing specificIgE antibody level (titer) in nasal fluid or in serum and/or reducingbasophil histamine release of blood.

Embodiment 94

The method according to embodiment 91, wherein the one or moresymptom(s) are symptoms associated with allergic conjunctivitis.

Embodiment 95

The method according to embodiment 94, wherein the method comprisesreducing the intensity of itchy eyes, redness in the white of the eyesand/or watery eyes; reducing the eosinophilic count in conjunctivaltissue scrapings; reducing specific IgE antibody level (titer) inconjunctival tissue scrapings or in serum and/or reducing basophilhistamine release of blood.

Embodiment 96

The method according to embodiment 91, wherein the one or moresymptom(s) are symptoms associated with allergic asthma.

Embodiment 97

The method according to embodiment 96, wherein the method comprisesreducing the intensity and/or number of coughs within a given period(e.g. daily, weekly, monthly); reducing the intensity of wheezes;improving being short of breath; improving lung function; reducingspecific IgE antibody level (titer) in lung fluid or in serum and/orreducing basophil histamine release of blood.

Embodiment 98

The method according to embodiment 91, wherein the one or moresymptom(s) are symptoms associated with atopic dermatitis.

Embodiment 99

The method according to embodiment 98, wherein the method comprisesreducing itch intensity of the skin; reducing eczema score and/orreducing number of (peripheral) blood eosinophils.

Embodiment 100

The method according to any one of embodiments 88 to 99, wherein themethod comprises reducing the subject's need for concomitant treatmentwith corticosteroids or H1 antihistamines to reduce, relieve or suppressone or more symptoms of the immune response.

Embodiment 101

The method according to any one of embodiments 88 to 100, wherein thedust mite allergy is clinically presented as atopic dermatitis,urticaria, contact dermatitis, allergic conjunctivitis, allergicrhinitis, allergic asthma, anapylaxis, and/or hay fever.

Embodiment 102

The method according to any one of embodiments 88 to 101, wherein themethod decreases, reduces, suppresses or inhibits atopic dermatitis,urticaria, contact dermatitis, allergic conjunctivitis, allergicrhinitis, allergic asthma, anaphylaxis, and/or hay fever.

Embodiment 103

The method according to any one of embodiments 88 to 102, wherein themethod comprises inducing or increasing an IgG antibody response in thesubject to an allergen of a dust mite.

Embodiment 104

The method according to any one of embodiments 88 to 103, wherein themethod comprises decreasing an IgE antibody response in the subject toan allergen of a dust mite.

Embodiment 105

The method according to any one of embodiments 88 to 105, wherein themethod comprises decreasing a T cell response in the subject to anallergen of a dust mite.

Embodiment 106

The method according to any one of embodiments 88 to 105, wherein thesubject is sensitized to an allergen of a dust mite (e.g. has specificIgE antibodies against an allergen of a dust mite and/or has a T cellresponse against an allergen of a dust mite).

Embodiment 107

The method according to any one of embodiments 88 to 106, wherein thedust mite is of the genus Dermatophagoides.

Embodiment 108

The method according to any one of embodiments 88 to 107, wherein theallergen of a dust mite is Der p 1, Der p 2, Der f 1 and/or Der f 2.

Embodiment 109

The method according to any one of embodiments 88 to 108, wherein thetreatment comprises repeated administration of the composition inweekly, bi-weekly, monthly or quarterly intervals.

Embodiment 110

The method according to any one of embodiments 88 to 109, wherein thetreatment is by immunotherapy.

Embodiment 111

The method according to any one of embodiments 88 to 110, wherein asingle dose of each single peptide of the composition is in the range of1 to 1000 nanomoles.

Embodiment 112

The method according to any one of embodiments 88 to 111, wherein theadministration comprises administering a volume of about 50 to 150microliters of the composition (e.g. by intradermal administration).

Embodiment 113

The method according to any one of embodiments 88 to 112, wherein theadministration is by a route of administration selected from any one ofsubcutaneous, intradermal, epicutaneous, rectal, topical, sublingual,oral, buccal, intranasal, respiratory and intralymphatic route.

Embodiment 114

The method according to any one of embodiments 88 to 113, wherein thesubject is a human, a pet such as a dog or a cat or a domestic animalsuch as a horse.

Embodiment 115

A composition according to any one of embodiments 1-84 for use in amethod according to any one of embodiments 88-114.

Embodiment 116

Use of a composition according to any one of embodiments 1-84 for thepreparation of a medicament for use in a method according to any one ofembodiments 88-114.

Embodiment 117

An in vitro method of determining whether T cells of a subject in needof treatment recognize a composition as defined in any of embodiments 1to 784, comprising contacting T cells obtained from the subject withsaid composition or a single peptide thereof and detecting whether the Tcells are stimulated by said composition or single peptide.

Embodiment 118

The method of embodiment 117 carried out to determine whether a subjecthas, or is at risk of developing, an allergy to a dust mite allergen.

Embodiment 119

A diagnostic kit comprising a composition according to any one ofembodiments 1-84.

The invention is still further described by the following embodiments A1to A191:

Embodiment A1

A composition comprising a peptide combination comprising three peptidesor more, wherein each peptide of the combination is independentlyselected from:

(a) any of the peptides consisting of an amino acid sequence of SEQ IDNOS:249 (peptide 002), 251 (peptide 010), 252 (peptide 011), 253(peptide 012), 254 (peptide 022), 255 (peptide 025), 256 (peptide 031),9 (peptide 041), 10 (peptide 042), 11 (peptide 043), 12 (peptide 044),15 (peptide 047), 17 (peptide 049), 18 (peptide 050), 20 (peptide 052),21 (peptide 053), (peptide 054), 23 (peptide 055), 26 (peptide 058), 29(peptide 061), 238 (peptide 066), 42 (peptide 072), 46 (peptide 075), 49(peptide 078), 52 (peptide 081), 58 (peptide 087), 60 (peptide 089), 61(peptide 090), 62 (peptide 091), 63 (peptide 092), 67 (peptide 096), 70(peptide 099), 71 (peptide 100), 72 (peptide 101), 73 (peptide 102), 77(peptide 106), 79 (peptide 108), 81 (peptide 109), 82 (peptide 110), 257(peptide 117), 258 (peptide 122), 266 (peptide 123), 267 (peptide 124),269 (peptide 125), 270 (peptide 126), 268 (peptide 130), 271 (peptide131), 259 (peptide 203B), 264 (peptide 26B), 90, 98, 99, 280, 102, 161,281, 282, 103, 105, 106, 166, 111, 112, 284, 114, 115, 173, 174, 285,117, 176, 120, 121, 180, 128, 129, 272, 187, 188, 273, 191, 133, 192,274, 140, 199, 226, 275, 227, 205, 206, 229, 230, 276, 277, 208, 233,278, 210, 234, 242, 243, 279, 221, 245, 246, 166, 223, 247, 224 or 248;or (b) a variant sequence, a derivative or a salt of any of the peptidesin (a).

Embodiment A2

The composition according to embodiment A1, wherein at least one of thepeptides of the peptide combination is a peptide of allergen der p 1 orallergen der f 1 and is selected from:

(a) any of the peptides consisting of an amino acid sequence of SEQ IDNOS:251 (peptide 010), 252 (peptide 011), 253 (peptide 012), 254(peptide 022), 255 (peptide 025), 9 (peptide 041), 10 (peptide 042), 11(peptide 043), 12 (peptide 044), 17 (peptide 049), 18 (peptide 050), 20(peptide 052), 21 (peptide 053), 22 (peptide 054), 23 (peptide 055), 26(peptide 058), 29 (peptide 061), 42 (peptide 072), 46 (peptide 075), 49(peptide 078), 52 (peptide 081), 58 (peptide 087), 258 (peptide 122),266 (peptide 123), 267 (peptide 124), 268 (peptide 130), 259 (peptide203B), 90, 98, 99, 280, 102, 161, 281, 282, 103, 105, 106, 283, 166,111, 112, 284, 114, 115, 173, 174, 285, 117, 176, 120, 121, 180, 128,129, 272, 187, 188, 273, 191, 133, 274, 140 or 199; or (b) a variantsequence, a derivative or a salt of any of the peptides in (a).

Embodiment A3

The composition according to any one of the preceding embodiments A1 toA2, wherein at least one peptide of the peptide combination is a peptideof allergen Der p 2 or allergen Der f 2 and is selected from:

(a) any of the peptides consisting of an amino acid sequence of SEQ IDNOS:249 (peptide 002), 253 (peptide 012), 256 (peptide 031), 238(peptide 066), 60 (peptide 089), 61 (peptide 090), 62 (peptide 091), 63(peptide 092), 67 (peptide 096), 70 (peptide 099), 71 (peptide 100), 72(peptide 101), 73 (peptide 102), 77 (peptide 106), 79 (peptide 108), 81(peptide 109), 82 (peptide 110), 269 (peptide 125), 270 (peptide 126),285 (peptide 131), 264 (peptide 26B), 226, 275, 227, 205, 206, 229, 230,276, 277, 208, 233, 192, 278, 210, 234, 242, 243, 279, 221, 245, 246,166, 223, 247, 224 or 248; or (b) a variant sequence, a derivative or asalt of any of the peptides in (a).

Embodiment A4

The composition according to any of the preceding embodiments A1 to A3,wherein at least three peptides are independently selected from any ofthe peptides denoted with the rating “A” as set out in Table 12.

Embodiment A5

The composition according to embodiment A4, wherein at least threepeptides are independently selected from:

(a) any of the peptides comprising an amino acid sequence of SEQ IDNOS:249 (peptide 002), 251 (peptide 010), 252 (peptide 011), 253(peptide 012), 256 (peptide 031), 10 (peptide 042), 11 (peptide 043), 12(peptide 044), 17 (peptide 049), 18 (peptide 050), 21 (peptide 053), 22(peptide 054), 26 (peptide 058), 29 (peptide 061), 52 (peptide 081), 58(peptide 087), 61 (peptide 090), 62 (peptide 091), 67 (peptide 096), 70(peptide 099), 73 (peptide 102), 81 (peptide 109), 82 (peptide 110), 258(peptide 122), 266 (peptide 123), 267 (peptide 124), 269 (peptide 125),270 (peptide 126), 268 (peptide 130), 271 (peptide 131), 259 (peptide203B), 264 (peptide 26B), 280, 281, 282, 166, 284, 285, 272, 273, 274,275, 276 or 277; or (b) a variant sequence, a derivative or a salt ofany of the peptides in (a).

Embodiment A6

The composition according to any of the preceding embodiments A1 to A5,wherein at least three peptides are selected from any of the “firstchoice peptides” set out in Table 15.

Embodiment A7

The composition according to embodiment A6, wherein at least threepeptides are selected from:

(a) any of the peptides consisting of an amino acid sequence of SEQ IDNOS: 253 (peptide 012), 256 (peptide 031), 270 (peptide 126), 17(peptide 049), 266 (peptide 123), 18 (peptide 050), 267 (peptide 124),21 (peptide 053), 22 (peptide 054), 268 (peptide 130), 26 (peptide 058),52 (peptide 081), 61 (peptide 090), 62 (peptide 091), 67 (peptide 096),271 (peptide 131), 70 (peptide 099), 269 (peptide 125), 73 (peptide102), 81 (peptide 109) or 82 (peptide 110); or (b) a variant sequence, aderivative or a salt of any of the peptides in (a).

Embodiment A8

The composition according to any of the preceding embodiments A1 to A7,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 22 (peptide 054) or 268 (peptide130), or a variant sequence, a derivative or a salt thereof.

Embodiment A9

The composition according to any of the preceding embodiments A1 to A8,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 70 (peptide 099), 269(peptide 125), 82 (peptide 110), 264 (peptide 26B), 253 (peptide 012),166, 246, 223, 247, 224 or 248, or a variant sequence, a derivative or asalt thereof.

Embodiment A10

The composition according to any of the preceding embodiments A1 to A9,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS:, 7 (peptide 096), 271(peptide 131), 79 (peptide 108), 256 (peptide 031), 270 (peptide 126),242 or 279, or a variant sequence, a derivative thereof or a saltthereof.

Embodiment A11

The composition according to any of the preceding embodiments A1 to A10,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 26 (peptide 058), 133, 192, or274, or a variant sequence, a derivative or a salt thereof.

Embodiment A12

The composition according to any of the preceding embodiments A1 to A11,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 17 (peptide 049), 266 (peptide123), SEQ ID NO: 46 (peptide 075), SEQ ID NO: 173, 174 or 285, or avariant sequence, a derivative or a salt thereof.

Embodiment A13

The composition according to any of the preceding embodiments A1 to A12,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 12 (peptide 044), 105, 106 or283, or a variant sequence, a derivative or a salt thereof.

Embodiment A14

The composition according to any of the preceding embodiments A1 to A13,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NO: 251 (peptide 010), 252 (peptide11), 58 (peptide 087), 29 (peptide 061), 140 or 199, or a variantsequence, a derivative or a salt thereof.

Embodiment A15

The composition according to any of the preceding embodiments A1 to A14,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 62 (peptide 091) or 208,or a variant sequence, a derivative or a salt thereof.

Embodiment A16

The composition according to any of the preceding embodiments A1 to A15,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 18 (peptide 050), 258 (peptide122), 267 (peptide 124), 117 or 176, or a variant sequence, a derivativeor a salt thereof.

Embodiment A17

The composition according to any of the preceding embodiments A1 to A16,wherein at least one peptide of the combination consists of an aminoacid sequence of SEQ ID NO: 9 (peptide 041), 98, 99 or 280, or a variantsequence, a derivative or a salt thereof.

Embodiment A18

The composition according to any of the preceding embodiments A1 to A17,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 10 (peptide 042), 259(HDM203B), 102, 161, 281 or 282, or a variant sequence, a derivative ora salt thereof.

Embodiment A19

The composition according to any of the preceding embodiments A1 to A18,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 11 (peptide 043), SEQ ID NO:103, 281 or 282, or a variant sequence, a derivative or a salt thereof.

Embodiment A20

The composition according to any of the preceding embodiments A1 to A19,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 42 (peptide 072), 254 (peptide022) or 166, or a variant sequence, a derivative or a salt thereof.

Embodiment A21

The composition according to any of the preceding embodiments A1 to A20,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 15 (peptide 047), 111, 112 or284, or a variant sequence, a derivative or a salt thereof.

Embodiment A22

The composition according to any of the preceding embodiments A1 to A21,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 265 (peptide 025), 115, 173 or285, or a variant sequence, a derivative or a salt thereof.

Embodiment A23

The composition according to any of the preceding embodiments A1 to A22,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 20 (peptide 052) 49 (peptide078), 121 or 180, or a variant sequence, a derivative or a salt thereof.

Embodiment A24

The composition according to any of the preceding embodiments A1 to A23,wherein one peptide of the combination consists of an amino acidsequence of SEQ ID NO: 21 (peptide 053), or a variant sequence, aderivative or a salt thereof.

Embodiment A25

The composition according to any of the preceding embodiments A1 to A24,wherein at least one peptide of the combination consists of an aminoacid sequence selected from SEQ ID NOS: 23 (peptide 055), 52 (peptide081), 128, 129, 272, 187, 188 or 273, or a variant sequence, aderivative or a salt thereof.

Embodiment A26

The composition according to any of the preceding embodiments A1 to A25,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 61 (peptide 090), 73(peptide 102), 205, 206, 229, 230, 276 or 277, or a variant sequence, aderivative or a salt thereof.

Embodiment A27

The composition according to any of the preceding embodiments A1 to A26,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 249 (peptide 002), 206 or230, or a variant sequence, a derivative or a salt thereof.

Embodiment A28

The composition according to any of the preceding embodiments A1 to A27,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 63 (peptide 092), 233,210, 234 or 278, or a variant sequence, a derivative or a salt thereof.

Embodiment A29

The composition according to any of preceding embodiments A1 to A28,wherein at least one peptide of the combination consists of an aminoacid sequence selected from any of SEQ ID NOS: 81 (peptide 109), 221 or245, or a variant sequence, a derivative or a salt thereof.

Embodiment A30

The composition according to any of embodiments A1 to A29, wherein afirst peptide of the combination consists of an amino acid sequenceselected from SEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82(peptide 110), 264 (peptide 26B), 253 (peptide 012), 246, 223, 247, 224or 248, or a variant sequence, a derivative or a salt thereof; and asecond peptide of the combination consists of an amino acid sequenceselected from SEQ ID NOS: 26 (peptide 058), 133, 192, or 274, or avariant sequence, a derivative or a salt thereof.

Embodiment A31

The composition according to any of embodiments A1 to A29, wherein afirst peptide of the combination consists of an amino acid sequenceselected from any of SEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82(peptide 110), 264 (peptide 26B), 253 (peptide 012), 246, 223, 247, 224or 248, or a variant sequence, a derivative or a salt thereof; and asecond peptide of the combination consists of an amino acid sequenceselected from SEQ ID NOS: 12 (peptide 044) 105 or 106, or a variantsequence, a derivative or a salt thereof.

Embodiment A32

The composition according to any of embodiments A1 to A29, wherein afirst peptide of the combination consists of an amino acid sequenceselected from SEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82(peptide 110), 264 (peptide 26B), 253 (peptide 012), 246, 223, 247, 224or 248, or a variant sequence, a derivative or a salt thereof; and asecond peptide of the combination consists of an amino acid sequenceselected from SEQ ID NOS: 251 (peptide 010), 252 (peptide 011), 58(peptide 087) 29 (peptide 061), 140 or 199, or a variant sequence, aderivative or a salt thereof.

Embodiment A33

The composition according to embodiment 31, wherein the peptidecombination comprises at least three peptides, wherein a first peptideand a second peptide of the combination are selected from any of SEQ IDNOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264 (peptide26B), 253 (peptide 012), 246, 223, 247, 224 or 248, or a variantsequence, a derivative or a salt thereof; and a third peptide of thecombination consists of an amino acid sequence selected from SEQ ID NOS:12 (peptide 044) 105, 106 or 283, or a variant sequence, a derivative ora salt thereof (peptides of peptide combination number 13 set out inTable 14).

Embodiment A34

The composition according to embodiment A33, wherein the peptidecombination comprises at least three peptides consisting of an aminoacid sequence of SEQ ID NOS: 12 (peptide 044), 70 (peptide 099) and 82(peptide 110), respectively, or a variant sequence, a derivative or asalt thereof. (peptides of peptide combination number 13 set out inTable 14)

Embodiment A35

The composition according to any of embodiments A31 or 32, wherein thepeptide combination comprises at least three peptides, wherein a firstpeptide consists of an amino acid sequence selected from SEQ ID NOS: 70(peptide 099), 269 (peptide 125), 82 (peptide 110), 264 (peptide 26B),253 (peptide 012), 246, 223, 247, 224 or 248, or a variant sequence, aderivative or a salt thereof; a second peptide consists of an amino acidsequence selected from SEQ ID NOS: 12 (peptide 044) 105, 106 or 283, ora variant sequence, a derivative or a salt thereof; and a third peptideconsists of an amino acid sequence selected from SEQ ID NO: 251 (peptide010), 252 (peptide 11), 58 (peptide 087), 29 (peptide 061), 140 or 199,or a variant sequence, a derivative and a salt thereof (peptides ofpeptide combination number 16 set out in Table 14).

Embodiment A36

The composition according to embodiment A35, wherein the peptidecombination comprises at least three peptides consisting of an aminoacid sequence of SEQ ID NOS: 12 (peptide 044), 82 (peptide 110) and 251(peptide 010), respectively, or a variant sequence, a derivative or asalt thereof (peptides of peptide combination number 16 set out in Table14).

Embodiment A37

The composition according to embodiment A32, wherein the peptidecombination comprises at least four peptides, wherein a first peptideand a second peptide consist of an amino acid sequence selected from SEQID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a third peptideconsists of an amino acid sequence selected from SEQ ID NO: 251 (peptide010), 252 (peptide 11), 58 (peptide 087), 29 (peptide 061), 140 or 199,or a variant sequence, a derivative or a salt thereof; and a fourthpeptide consists of an amino acid sequence selected from SEQ ID NOS: 18(peptide 050), 258 (peptide 122), 267 (peptide 124), 117 or 176, avariant sequence, a derivative or a salt thereof (peptides of peptidecombination number 20 set out in Table 14).

Embodiment A38

The composition according to embodiment A37, wherein the peptidecombination comprises at least four peptides consisting of an amino acidsequence of SEQ ID NOS: 18 (peptide 050), 82 (peptide 110), 251 (peptide010) and 70 (peptide 070), respectively, or a variant sequence, aderivative or a salt thereof (peptides of peptide combination number 20set out in Table 14).

Embodiment A39

The composition according to any of embodiments A30 to A38, wherein afurther peptide of the peptide combination comprises of an amino acidsequence selected from SEQ ID NOS: 70 (peptide 099), 269 (peptide 125),82 (peptide 110), 264 (peptide 26B), 253 (peptide 012), 246, 223, 247,224 or 248, or a variant sequence, a derivative or a salt thereof.

Embodiment A40

The composition according to any of embodiments A30 to A39, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 22 (peptide 054) or 268 (peptide130), or a variant sequence, a derivative or a salt thereof.

Embodiment A41

The composition according to any of embodiments A30 to A40, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS:, 7 (peptide 096), 271 (peptide 131),79 (peptide 108), 256 (peptide 031), 270 (peptide 126), 242 or 279, or avariant sequence, a derivative or a salt thereof.

Embodiment A42

The composition according to any of embodiments A30 to A41, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 26 (peptide 058), 133, 192 or 274, ora variant sequence, a derivative or a salt thereof.

Embodiment A43

The composition according to any of embodiments A30 to A42, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 17 (peptide 049), 266 (peptide 123),46 (peptide 075), 173, 174 or 285, or a variant sequence, a derivativeor a salt thereof.

Embodiment A44

The composition according to any of embodiments A30 to A43, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 12 (peptide 044), 105, 106 or 283, ora variant sequence, a derivative or a salt thereof.

Embodiment A45

The composition according to any of embodiments A30 to A44, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NO: 251 (peptide 010), 252 (peptide 11),58 (peptide 087), 30 (peptide 061), 140 or 199, or a variant sequence, aderivative or a salt thereof.

Embodiment A46

The composition according to any of embodiments A30 to A45, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 62 (peptide 091) or 208, or a variantsequence, a derivative or a salt thereof.

Embodiment A47

The composition according to any of embodiments A30 to A46, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 18 (peptide 050), 258 (peptide 122),267 (peptide 124), 117 or 176, or a variant sequence, a derivative or asalt thereof.

Embodiment A48

The composition according to any of embodiments A30 to A47, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NO: 9 (peptide 041), 98, 99 or 280, or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A49

The composition according to any of embodiments A30 to A48, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 10 (peptide 042), 259 (HDM203B), 102,161, 281 or 282, a variant sequence, a derivative or a salt thereof.

Embodiment A50

The composition according to any of embodiments A30 to A49, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 11 (peptide 043) or SEQ ID NO: 103,or a variant sequence, a derivative or a salt thereof.

Embodiment A51

The composition according to any of embodiments A30 to A50, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 42 (peptide 072), 254 (peptide 022)or 166, or a variant sequence, a derivative or a salt thereof.

Embodiment A52

The composition according to any of embodiments A30 to A51, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 15 (peptide 047), 111, 112 or 284, ora variant sequence, a derivative or a salt thereof.

Embodiment A53

The composition according to any of embodiments A30 to A52, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 265 (peptide 025), 115, 173 or 285,or a variant sequence, a derivative or a salt thereof.

Embodiment A54

The composition according to any of embodiments A30 to A53, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 20 (peptide 052) 49 (peptide 078),121 or 180, or a variant sequence, a derivative or a salt thereof.

Embodiment A55

The composition according to any of embodiments A30 to A54, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NO: 21 (peptide 053), or a variantsequence, a derivative or a salt thereof.

Embodiment A56

The composition according to any of embodiments A30 to A55, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 23 (peptide 055), 52 (peptide 081),128, 129, 272, 187, 188 or 273, or a variant sequence, a derivative or asalt thereof.

Embodiment A57

The composition according to any of embodiments A30 to A56, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 61 (peptide 090), 73 (peptide 102),205, 206, 229, 230, 276 or 277, or a variant sequence, a derivative or asalt thereof.

Embodiment A58

The composition according to any of embodiments A30 to A57, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 249 (peptide 002), 206 or 230, or avariant sequence, a derivative or a salt thereof.

Embodiment A59

The composition according to any of embodiments A30 to A58, wherein afurther peptide of the peptide combination consists of an amino acidsequence selected from SEQ ID NOS: 63 (peptide 092), 233, 210, 234 or278, or a variant sequence, a derivative or a salt thereof.

Embodiment A60

The composition according to any of embodiments A30 to A59, wherein thepeptide combination comprises at least one peptide consisting of anamino acid sequence derived from allergen Der p 4, or a variantsequence, a derivative or a salt thereof; such as a peptide consistingof an amino acid sequence selected from SEQ ID NO: 257 (peptide 117), ora variant sequence, a derivative or a salt thereof.

Embodiment A61

The composition according to any of the preceding embodiments, whereinthe peptide combination consists of or comprises the peptides of apeptide combination selected from peptide combination number 3, 4, 5, 6,7, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 23, 24, 25, 17, 17a, 17b,17c, 17d, 17f and 17p set out in Table 14, wherein the amino acidsequences of said peptides are set out in Table 12, or variantsequences, derivatives or salts thereof.

Embodiment A62

The composition according to any of embodiments A30 or A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide consists of an amino acid sequence selected fromSEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a second peptideconsists of an amino acid sequence selected from SEQ ID NOS: 26 (peptide058) 133, 192 or 274, or a variant sequence, a derivative or a saltthereof; a third peptide consists of an amino acid sequence of SEQ IDNO: 9 (peptide 041), 98, 99 or 280, or a variant sequence, a derivativeor a salt thereof; a fourth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 17 (peptide 049), 266 (peptide 123), 46(peptide 075), 173, 174 or 285, or a variant sequence, a derivative or asalt thereof; and a fifth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 81 (peptide 109), 221 or 245 a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 17 set out in Table 14).

Embodiment A63

The composition according to embodiment A62, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NOS: 82 (peptide 110), 26 (peptide 058), 9 (peptide041), 46 (peptide 075) and 81 (peptide 109), respectively, or a variantsequence, a derivative or a salt thereof (peptide combination number 17set out in Table 14).

Embodiment A64

The composition according to any of embodiments A30 and A33 to 61,wherein the peptide combination comprises at least five peptides,wherein a first peptide consists of an amino acid sequence selected fromSEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a second peptideconsists of an amino acid sequence selected from SEQ ID NOS: 26 (peptide058) 133, 192 or 274, or a variant sequence, a derivative or a saltthereof; a third peptide consists of an amino acid sequence selectedfrom SEQ ID NOS: 22 (peptide 054) or 268 (peptide 130), or a variantsequence, a derivative or a salt thereof; a fourth peptide consists ofan amino acid sequence selected from SEQ ID NOS: 17 (peptide 049), 266(peptide 123), 46 (peptide 075), 173, 174 or 285, a variant sequence, aderivative or a salt thereof; and a fifth peptide consists of an aminoacid sequence selected from SEQ ID NOS: 81 (peptide 109), 221 or 245, ora variant sequence, a derivative or a salt thereof (peptides of peptidecombination number 17a set out in Table 14).

Embodiment A65

The composition according to embodiment A64, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NO: 22 (peptide 054), 26 (peptide 058), 46 (peptide075), 81 (peptide 109) and 82 (peptide 110), respectively, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 17a set out in Table 14).

Embodiment A66

The composition according to any of embodiments A30 and A33 to A61,wherein the peptide combination comprises at least 5 peptides, wherein afirst peptide consists of an amino acid sequence selected from SEQ IDNOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264 (peptide26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or a variantsequence, a derivative or a salt thereof; a second peptide consists ofan amino acid sequence selected from SEQ ID NOS: 26 (peptide 058) 133,192 or 274, or a variant sequence, a derivative or a salt thereof; athird peptide consists of an amino acid sequence of SEQ ID NO: 9(peptide 041), 98, 99 or 280, or a variant sequence, a derivative or asalt thereof; a fourth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 23 (peptide 055), 52 (peptide 081), 128, 129,272, 187, 188 or 273, or a variant sequence, a derivative or a saltthereof; and a fifth peptide consists of an amino acid sequence selectedfrom SEQ ID NOS: 81 (peptide 109), 221 or 245, or a variant sequence, aderivative or a salt thereof (peptides of peptide combination number 17bset out in Table 14).

Embodiment A67

The composition according to embodiment A66, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NO: 9 (peptide 041), 26 (peptide 058), 52 (peptide081), 81 (peptide 109) and 82 (peptide 110), respectively, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 17b set out in Table 14).

Embodiment A68

The composition according to any of embodiments A30 and A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide consists of an amino acid sequence selected fromSEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a second peptideconsists of an amino acid sequence selected from SEQ ID NOS: 26 (peptide058) 133, 192 or 274, or a variant sequence, a derivative or a saltthereof; a third peptide consists of an amino acid sequence of SEQ IDNO: 9 (peptide 041), 98, 99 or 280, or a variant sequence, a derivativeor a salt thereof; a fourth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 17 (peptide 049), 266 (peptide 123), 46(peptide 075), 173, 174 or 285, or a variant sequence, a derivative or asalt thereof; and a fifth peptide consists of an amino acid sequence ofan amino acid sequence selected from SEQ ID NOS: 62 (peptide 091) or208, or a variant sequence, a derivative or a salt thereof (peptides ofpeptide combination number 17c set out in Table 14).

Embodiment A69

The composition according to embodiment A68, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NO: 9 (peptide 041), 26 (peptide 058), 46 (peptide075), 62 (peptide 091) and 82 (peptide 110), respectively, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 17c set out in Table 14).

Embodiment A70

The composition according to any of embodiments A30 and A33 to A61,wherein the peptide combination comprises at least 5 peptides, wherein afirst peptide consists of an amino acid sequence selected from SEQ IDNOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264 (peptide26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or a variantsequence, a derivative or a salt thereof; a second peptide consists ofan amino acid sequence selected from SEQ ID NOS: 26 (peptide 058) 133,192 or 274, or a variant sequence, a derivative or a salt thereof; athird peptide consists of an amino acid sequence selected from SEQ IDNOS: 22 (peptide 054) or 268 (peptide 130), or a variant sequence, aderivative or a salt thereof; a fourth peptide consists of an amino acidsequence selected from SEQ ID NOS: 23 (peptide 055), 52 (peptide 081),128, 129, 272, 187, 188 or 273, or a variant sequence, a derivative or asalt thereof; and a fifth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 62 (peptide 091) or 208, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 17d set out in Table 14).

Embodiment A71

The composition according to embodiment A70, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NO: 22 (peptide 054), 26 (peptide 058), 52 (peptide081), SEQ ID NO: 62 (peptide 091) and SEQ ID NO: 82 (peptide 110),respectively, or a variant sequence, a derivative or a salt thereof.(peptides of peptide combination number 17d set out in Table 14).

Embodiment A72

The composition according to any of embodiments A30 and A33 to A61,wherein the peptide combination comprises at least 5 peptides, wherein afirst peptide consists of an amino acid sequence selected from SEQ IDNOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264 (peptide26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or a variantsequence, a derivative or a salt thereof; a second peptide consists ofan amino acid sequence selected from SEQ ID NOS: 26 (peptide 058) 133,192 or 274, or a variant sequence, a derivative or a salt thereof; athird peptide consists of an amino acid sequence selected from SEQ IDNOS: 22 (peptide 054) or 268 (peptide 130), or a variant sequence, aderivative or a salt thereof; a fourth peptide consists of an amino acidsequence selected from SEQ ID NOS: 17 (peptide 049), 266 (peptide 123),46 (peptide 075), 173, 174 or 285, or a variant sequence, a derivativeor a salt thereof; and a fifth peptide consists of an amino acidsequence selected from SEQ ID NOS: 256 (peptide 031), 7 (peptide 096),271 (peptide 131), 79 (peptide 108), 270 (peptide 126), 242 or 279, or avariant sequence, a derivative or a salt thereof (peptides of peptidecombination number 17f set out in Table 14).

Embodiment A73

The composition according to embodiment A72, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NO: 26 (peptide 058), 46 (peptide 075), 82 (peptide110), 268 (peptide 130) and 271 (peptide 131), respectively or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 17f set out in Table 14).

Embodiment A74

The composition according to embodiment 72, wherein the second peptideconsisting of an amino acid sequence selected from SEQ ID NOS: 26(peptide 058) 133, 192 or 274, or a variant sequence, a derivative or asalt thereof is substituted by a peptide consisting of an amino acidsequence selected from SEQ ID NOS: 62 (peptide 091) or 208, or a variantsequence, a derivative or a salt thereof.

Embodiment A75

The composition according to embodiment A74, wherein the peptidecombination comprises at least five peptides, wherein a first peptideconsists of an amino acid sequence selected from SEQ ID NOS: 70 (peptide099), 269 (peptide 125), 82 (peptide 110), 264 (peptide 26B), 253(peptide 012), 166, 246, 223, 247, 224 or 248, or a variant sequence, aderivative or a salt thereof; a second peptide consists of an amino acidsequence selected from SEQ ID NOS: 62 (peptide 091) or 208, or a variantsequence, a derivative or a salt thereof; a third peptide consists of anamino acid sequence selected from SEQ ID NOS: 22 (peptide 054) or 268(peptide 130), or a variant sequence, a derivative or a salt thereof; afourth peptide consists of an amino acid sequence selected from SEQ IDNOS: 17 (peptide 049), 266 (peptide 123), 46 (peptide 075), 173, 174 or285, or a variant sequence, a derivative or a salt thereof; and a fifthpeptide consists of an amino acid sequence selected from SEQ ID NOS: 256(peptide 031), 7 (peptide 096), 271 (peptide 131), 79 (peptide 108), 270(peptide 126), 242 or 279, or a variant sequence, a derivative or a saltthereof (peptides of peptide combination number 17p set out in Table14).

Embodiment A76

The composition according to embodiment A75, wherein the peptidecombination consists of or comprises the five peptides consisting of anamino acid sequence of SEQ ID NO: 62 (peptide 091), 82 (peptide 110),266 (peptide 123), 268 (peptide 130) and 271 (peptide 131),respectively, or a variant sequence, a derivative or a salt thereof(peptides of peptide combination number 17p set out in Table 14).

Embodiment A77

The composition according to any of embodiments A31 or A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide consists of an amino acid sequence selected fromSEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a second peptideconsists of an amino acid sequence selected from SEQ ID NOS: 12 (peptide044) 105, 106 or 283, or a variant sequence, a derivative or a saltthereof; a third peptide consists of an amino acid sequence of SEQ IDNO: 71 (peptide 100), 226 or 275, or a variant sequence, a derivative ora salt thereof; a fourth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 17 (peptide 049), 266 (peptide 123), 46(peptide 075), 173, 174 or 285, or a variant sequence, a derivative or asalt thereof; and a fifth peptide consists of an amino acid sequence ofan amino acid sequence selected from SEQ ID NOS: 62 (peptide 090), 73(peptide 102), 60 (peptide 089), 205, 206, 229, 230, 276 or 277, or avariant sequence, a derivative or a salt thereof (peptides of peptidecombination number 23 set out in Table 14).

Embodiment A78

The composition according to embodiment A77, wherein the peptidecombination comprises at least the five peptides consisting of an aminoacid sequence of SEQ ID NOS: 82 (peptide 110), 12 (peptide 044), 73(peptide 102), 46 (peptide 075) and 71 (peptide 100), respectively, or avariant sequence, a derivative or a salt of any thereof (peptidecombination number 23 set out in Table 14).

Embodiment A79

The composition according to any of embodiments A31 or A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first and second peptide consist of an amino acid sequenceselected from SEQ ID NOs: 70 (peptide 099), 269 (peptide 125), 82(peptide 110), 264 (peptide 26B), 253 (peptide 012), 166, 246, 223, 247,224 or 248, or a variant sequence, a derivative or a salt thereof; athird peptide consists of an amino acid sequence selected from SEQ IDNOS: 12 (peptide 044) 105, 106 or 283, or a variant sequence, aderivative or a salt thereof; a fourth peptide consists of an amino acidsequence selected from SEQ ID NOS: 17 (peptide 049), 266 (peptide 123),46 (peptide 075), 173, 174 or 285, or a variant sequence, a derivativeor a salt thereof; and a fifth peptide consists of an amino acidsequence of SEQ ID NO: 9 (peptide 041), 98, 99 or 280, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 18 set out in Table 14).

Embodiment A80

The composition according to embodiment A80, wherein the peptidecombination comprises at least the five peptides consisting of an aminoacid sequence of SEQ ID NOS: 9 (041), 12 (044), 17 (049), SEQ ID NO: 70(peptide 099) and 82 (110), respectively, or a variant sequence, aderivative or a salt thereof. (peptides of peptide combination number 18set out in Table 14).

Embodiment A81

The composition according to any of embodiments A31 or A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide consists of an amino acid sequence selected fromSEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a second peptideconsists of an amino acid sequence selected from SEQ ID NOS: 12 (peptide044) 105, 106 or 283, or a variant sequence, a derivative or a saltthereof; a third peptide consists of an amino acid sequence selectedfrom SEQ ID NOS: 17 (peptide 049), 266 (peptide 123), 46 (peptide 075),173, 174 or 285, or a variant sequence, a derivative or a salt thereof;a fourth peptide consists of an amino acid sequence selected from SEQ IDNOS:62 (peptide 091) or 208, or a variant sequence, a derivative or asalt thereof; and a fifth peptide consists of an amino acid sequenceselected from SEQ ID NOS: 20 (peptide 052), 49 (peptide 078), 121 or180, or a variant sequence, a derivative or a salt thereof (peptides ofpeptide combination number 25 set out in Table 14).

Embodiment A82

The composition according to embodiment A83, wherein the peptidecombination comprises at least the five peptides consisting of an aminoacid sequence of SEQ ID NOS: 82 (peptide 110), 12 (peptide 044), 17(peptide 049), 62 (peptide 091) and 20 (peptide 052), respectively, or avariant sequence, a derivative or a salt thereof (peptides of peptidecombination number 25 set out in Table 14).

Embodiment A83

The composition according to any of embodiments A31 or A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide consists of an amino acid sequence selected fromSEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82 (peptide 110), 264(peptide 26B), 253 (peptide 012), 166, 246, 223, 247, 224 or 248, or avariant sequence, a derivative or a salt thereof; a second peptideconsists of an amino acid sequence selected from SEQ ID NOS: 12 (peptide044) 105, 106 or 283, or a variant sequence, a derivative or a saltthereof; a third peptide consists of an amino acid sequence selectedfrom SEQ ID NOS: 26 (peptide 058) 133, 192 or 274, or a variantsequence, a derivative or a salt thereof; a fourth peptide consists ofan amino acid sequence selected from SEQ ID NOS: 17 (peptide 049), 266(peptide 123), 46 (peptide 075), 173, 174 or 285, or a variant sequence,a derivative or a salt thereof; and a fifth peptide consists of an aminoacid sequence selected from SEQ ID NOS: 61 (peptide 090), 73 (peptide102), 60 (peptide 089), 205, 206, 229, 230, 276 or 277, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 10 set out in Table 14).

Embodiment A84

The composition according to embodiment A84, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NOS: 70 (peptide 099), 12 (peptide 044): 26 (peptide058), 46 (peptide 075), and 60 (peptide 089), respectively, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 10 set out in Table 14).

Embodiment A85

The composition according to any of embodiments A32 and A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide of the peptide combination consists of an aminoacid sequence selected from SEQ ID NOS: 70 (peptide 099), 269 (peptide125), 82 (peptide 110), 264 (peptide 26B), 253 (peptide 012), 166, 246,223, 247, 224 or 248, or a variant sequence, a derivative or a saltthereof, a second peptide of the peptide combination consists of anamino acid sequence selected from SEQ ID NOS: 251 (peptide 010), 252(peptide 011), 58 (peptide 087) 29 (peptide 061), 140 or 199, or avariant sequence, a derivative or a salt thereof; a third peptideconsists of an amino acid sequence selected from SEQ ID NOS: 256(peptide 031), 7 (peptide 096), 271 (peptide 131), 79 (peptide 108), 270(peptide 126), 242 or 279, or a variant sequence, a derivative or a saltthereof; a fourth peptide consists of an amino acid sequence of SEQ IDNO: 257 (peptide 117) or a variant sequence, a derivative or a saltthereof; and a fifth peptide consists of an amino acid sequence selectedfrom SEQ ID NOS: 18 (peptide 050), 258 (peptide 122), 267 (peptide 124),117 or 176, or a variant sequence, a derivative or a salt thereof(peptides of peptide combination number 3 set out in Table 14).

Embodiment A86

The composition according to embodiment A87, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NOS: 252 (peptide 011), 253 (peptide 012), 256(peptide 031), 257 (peptide 117) and 258 (peptide 122), respectively, ora variant sequence, or a derivative or a salt thereof. (peptides ofpeptide combination number 3 set out in Table 14).

Embodiment A87

The composition according to any of embodiments A32 and A33 to A61,wherein the peptide combination comprises at least five peptides,wherein a first peptide of the peptide combination consists of an aminoacid sequence selected from SEQ ID NOS: 70 (peptide 099), 269 (peptide125), 82 (peptide 110), 264 (peptide 26B), 253 (peptide 012), 166, 246,223, 247, 224 or 248, or a variant sequence, a derivative or a saltthereof; a second peptide of the peptide combination consists of anamino acid sequence selected from SEQ ID NOS: 251 (peptide 010), 252(peptide 011), 58 (peptide 087) 29 (peptide 061), 140 or 199, or avariant sequence, a derivative or a salt thereof; a third peptideconsists of an amino acid sequence selected from SEQ ID NOS: 256(peptide 031), 7 (peptide 096), 271 (peptide 131), 79 (peptide 108), 270(peptide 126), 242 or 279, or a variant sequence, a derivative or a saltthereof; a fourth peptide consists of an amino acid sequence selectedfrom SEQ ID NOS: 42 (peptide 072), 254 (peptide 022) or 166, or avariant sequence, a derivative or a salt thereof; and a fifth peptideconsists of an amino acid sequence selected from SEQ ID NOS: 18 (peptide050), 258 (peptide 122), 267 (peptide 124), 117 or 176, or a variantsequence, a derivative or a salt thereof (peptides of peptidecombination number 5 set out in Table 14).

Embodiment A88

The composition according to embodiment A88, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NOS: 252 (peptide 011), 253 (peptide 012), 254(peptide 022), 256 (peptide 031) and 258 (peptide 122), respectively, ora variant sequence, a derivative or a salt thereof. (peptides of peptidecombination number 5 set out in Table 14)

Embodiment A89

The composition according to embodiment A88, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NOS: 251 (peptide 010), 253 (peptide 012), 254(peptide 022), 256 (peptide 031) and SEQ ID NO: 258 (peptide 122),respectively, or a variant sequence, a derivative or a salt thereof.(peptides of peptide combination number 9 set out in Table 14)

Embodiment A90

The composition according to any of embodiments A32 and A33 to A63,wherein the peptide combination comprises at least five peptides,wherein a first and a second peptide consist of an amino acid sequenceselected from SEQ ID NOS: 70 (peptide 099), 269 (peptide 125), 82(peptide 110), 264 (peptide 26B), 253 (peptide 012), 166, 246, 223, 247,224 or 248, or a variant sequence, a derivative or a salt thereof; athird peptide consists of an amino acid sequence selected from SEQ IDNOS: 251 (peptide 010), 252 (peptide 011), 58 (peptide 087) 29 (peptide061), 140 or 199, or a variant sequence, a derivative or a salt thereof;a third peptide consists of an amino acid sequence selected from SEQ IDNOS: 256 (peptide 031), 7 (peptide 096), 271 (peptide 131), 79 (peptide108), 270 (peptide 126), 242 or 279, or a variant sequence, a derivativeor a salt thereof; a fourth peptide consists of an amino acid sequenceselected of SEQ ID NO: 9 (peptide 041), 98, 99 or 280, or a variantsequence, a derivative or a salt thereof; and a fifth peptide consistsof an amino acid sequence selected from SEQ ID NOS: 18 (peptide 050),258 (peptide 122), 267 (peptide 124), 117 or 176, or a variant sequence,a derivative or a salt thereof (peptides of peptide combination number19 set out in Table 14).

Embodiment A91

The composition according to embodiment A91, wherein the peptidecombination comprises at least five peptides consisting of an amino acidsequence of SEQ ID NOS: 251 (peptide 010), 9 (peptide 041), SEQ ID NO:18 (peptide 050), SEQ ID NO: 70 (peptide 099) and SEQ ID NO: 82 (peptide110), respectively, (peptides of peptide combination number 19 set outin Table 14), or a variant sequence, a derivative or a salt thereof.

Embodiment A92

The composition according to any of embodiments A1 to A29, wherein thepeptide combination comprises at least five peptides, wherein a firstpeptide consists of an amino acid sequence selected from SEQ ID NOS: 12(peptide 044) 105, 106 or 283, or a variant sequence, a derivative or asalt thereof; a second peptide consists of an amino acid sequenceselected from SEQ ID NOS: 20 (peptide 052) 49 (peptide 078), 121 or 180,or a variant sequence, a derivative or a salt thereof; a third peptideconsists of an amino acid sequence of SEQ ID NOS: 71 (peptide 100), 226or 275, or a variant sequence, a derivative or a salt thereof; a fourthpeptide consists of an amino acid sequence selected from any of SEQ IDNOS: 18 (peptide 050), 258 (peptide 122), 267 (peptide 124), 117 or 176,or a variant sequence, a derivative or a salt thereof; and a fifthpeptide consists of an amino acid sequence selected from SEQ ID NOS: 61(peptide 090), 73 (peptide 102), 60 (peptide 089), 205, 206, 229, 230,276 or 277, or a variant sequence, a derivative or a salt thereof(peptides of peptide combination number 24 set out in Table 14).

Embodiment A93

The composition according to embodiment A93, wherein the peptidecombination consists of or comprises the five following peptidesconsisting of an amino acid sequence of SEQ ID NO: 12 (peptide 044), 18(peptide 050), 49 (peptide 078), 71 (peptide 100) and 73 (peptide 102),respectively, or a variant sequence, a derivative or a salt thereof.(peptides of peptide combination number 24 set out in Table 14)

Embodiment A94

The composition according to any of embodiments A1 to A29, wherein thepeptide combination comprises at least five peptides, wherein a firstpeptide consists of an amino acid sequence selected from SEQ ID NOS: 70(peptide 099), 269 (peptide 125), 82 (peptide 110), 264 (peptide 26B),253 (peptide 012), 166, 246, 223, 247, 224 or 248, or a variantsequence, a derivative or a salt thereof; a second peptide consists ofan amino acid sequence selected from SEQ ID NOS: 249 (peptide 002), 206or 230, or a variant sequence, a derivative or a salt thereof; a thirdpeptide consists of an amino acid sequence of SEQ ID NOS: 42 (peptide072), 254 (peptide 022) or 166, or a variant sequence, a derivative or asalt thereof; a fourth peptide consists of an amino acid sequenceselected from any of SEQ ID NOS: 18 (peptide 050), 258 (peptide 122),267 (peptide 124), 117 or 176, or a variant sequence, a derivative or asalt thereof; and a fifth peptide consists of amino acid sequence 257(peptide 117), a variant sequence, a derivative or a salt thereof(peptides of peptide combination number 4 set out in Table 14).

Embodiment A95

The composition according to embodiment A95, wherein the peptidecombination consists of or comprises the five following peptidesconsisting of an amino acid sequence of SEQ ID NO: 249 (peptide 002),253 (peptide 12), 254 (peptide 022), 257 (peptide 117) and 258 (peptide122), respectively, or a variant sequence, a derivative or a saltthereof. (peptides of peptide combination number 4 set out in Table 14).

Embodiment A96

The composition according to any of embodiments A62 to A95, wherein thepeptide combination comprises a peptide consisting of an amino sequenceof SEQ ID NO: 264 (peptide HDM 203B), 281 or 282, or a variant sequence,a derivative or a salt thereof.

Embodiment A97

The composition according to any of embodiments A62 to A96, wherein thepeptide combination comprises a peptide consisting of an amino sequenceof SEQ ID NO: 259 (peptide HDM 26B), or a variant sequence, a derivativeor a salt thereof.

Embodiment A98

The composition according to any of embodiments A62 to A97, wherein thecombination comprises at least one additional peptide independentlyselected from peptides consisting of an amino acid sequence selectedfrom SEQ ID NOS:249 (peptide 002), 251 (peptide 010), 252 (peptide 011),253 (peptide 012), 254 (peptide 022), 255 (peptide 025), 256 (peptide031), 9 (peptide 041), 10 (peptide 042), 11 (peptide 043), 12 (peptide044), 15 (peptide 047), 17 (peptide 049), 18 (peptide 050), 20 (peptide052), 21 (peptide 053), 22 (peptide 054), 23 (peptide 055), 26 (peptide058), 29 (peptide 061), 238 (peptide 066), 42 (peptide 072), 46 (peptide075), 49 (peptide 078), 52 (peptide 081), 58 (peptide 087), 60 (peptide089), 61 (peptide 090), 62 (peptide 091), 63 (peptide 092), 67 (peptide096), 70 (peptide 099), 72 (peptide 101), 73 (peptide 102), 77 (peptide106), 79 (peptide 108), 81 (peptide 109), 82 (peptide 110), 257 (peptide117), 258 (peptide 122), 266 (peptide 123), 267 (peptide 124), 269(peptide 125), 270 (peptide 126), 268 (peptide 130), 271 (peptide 131),259 (peptide 203B), 264 (peptide 26B), 90, 98, 99, 280, 102, 161, 281,282, 103, 105, 106, 283, 111, 112, 284, 114, 115, 173, 174, 117, 176,120, 121, 180, 128, 129, 272, 187, 188, 273, 191, 133, 192, 274, 140,199, 226, 227, 205, 206, 229, 230, 276, 277, 208, 233, 278, 210, 234,242, 243, 279, 221, 245, 246, 223, 247, 224 or 248, or a variantsequence, a derivative or a salt thereof.

Embodiment A99

The composition according to any of the preceding embodiments A1 to A99,wherein a peptide consisting of an amino acid sequence set out in Table12 is replaced by a substitute peptide specified for said peptide inTable 12, or a variant sequence thereof, a derivative thereof or a saltthereof.

Embodiment A100

The composition according to any of the preceding embodiments A1 toA100, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 17 (peptide 058) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 22 (peptide 054), 255(peptide 025), 49 (peptide 078), 133, 192 or 274, or a variant sequencethereof, a derivative thereof or a salt thereof.

Embodiment A101

The composition according to any of the preceding embodiments A1 toA101, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 46 (peptide 075) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 255 (peptide 025), 271,17 (peptide 049), 20 (peptide 052), 22 (peptide 054), 21 (peptide 053),49 (peptide 078) or 266 (peptide 123), or a variant sequence thereof aderivative thereof or a salt thereof.

Embodiment A102

The composition according to any of the preceding embodiments A1 toA101, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 82 (peptide 110) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 253 (peptide 012), 70(peptide 099), 264 (peptide 26B), 269 (peptide 125), 224 or 248, or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A103

The composition according to any of the preceding embodiments A1 toA102, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 268 (peptide 130) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 255 (peptide 025), 285,12 (peptide 044), 283, 22 (peptide 054) or 21 (peptide 053), or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A104

The composition according to any of the preceding embodiments A1 toA103, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 271 (peptide 131) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 256 (peptide 031), 81(peptide 109), or 67 (peptide 096) or a variant sequence thereof, aderivative thereof or a salt thereof.

Embodiment A105

The composition according to any of the preceding embodiments A1 toA104, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 81 (peptide 109) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NO: 256 (peptide 031), 67(peptide 096) or 271 (peptide 131), or a variant sequence thereof, aderivative thereof or a salt thereof.

Embodiment A106

The composition according to any of the preceding embodiments A1 toA105, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 17 (peptide 049) is replaced by a substitute The compositionaccording to any of the preceding embodiments, wherein the peptideconsisting of an amino acid sequence of SEQ ID NO: 46 (peptide 075), 266(peptide 123) or 174, or a variant sequence thereof, a derivativethereof or a salt thereof.

Embodiment A107

The composition according to any of the preceding embodiments A1 toA106, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 22 (peptide 054) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 255 (peptide 025), 285,12 (peptide 044), 283, 21 (peptide 053), 26 (peptide 058), 274, 46(peptide 075) or 268 (peptide 130), or a variant sequence thereof, aderivative thereof or a salt thereof.

Embodiment A108

The composition according to any of the preceding embodiments A1 toA107, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 67 (peptide 096) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 256 (peptide 031), 81(peptide 109) or 271 (peptide 131), or a variant sequence thereof, aderivative thereof or a salt thereof.

Embodiment A109

The composition according to any of the preceding embodiments A1 toA108, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 12 (peptide 044) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 22 (peptide 054), 268(peptide 130) or 283, or a variant sequence thereof, a derivativethereof or a salt thereof.

Embodiment A110

The composition according to any of the preceding embodiments A1 toA109, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 15 (peptide 050) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 254 (peptide 022), 26(peptide 058), 274, 52 (peptide 081), 258 (peptide 122) or 267 (peptide124), or a variant sequence thereof, a derivative thereof or a saltthereof.

Embodiment A111

The composition according to any of the preceding embodiments A1 toA110, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 256 (peptide 031) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 81 (peptide 109), 271(peptide 131), 67 (peptide 096) or 270 (peptide 126), or a variantsequence thereof, a derivative thereof or a salt thereof.

Embodiment A112

The composition according to any of the preceding embodiments A1 toA111, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 251 (peptide 010) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 252 (peptide 011), 58(peptide 087) or 29 (peptide 061), or a variant sequence thereof, aderivative thereof or a salt thereof.

Embodiment A113

The composition according to any of the preceding embodiments A1 toA112, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 258 (peptide 122) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 18 (peptide 050), 52(peptide 081) or 267 (peptide 124), or a variant sequence thereof, aderivative thereof or a salt thereof.

Embodiment A114

The composition according to any of the preceding embodiments A1 toA113, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 253 (peptide 012) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 256 (peptide 031), 70(peptide 099), 81 (peptide 109), 82 (peptide 110) or 269 (peptide 125),or a variant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A115

The composition according to any of the preceding embodiments A1 toA114, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 73 (peptide 102) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 249 (peptide 002), 60(peptide 089), 61 (peptide 090), 276, 277 or 82 (peptide 110), or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A116

The composition according to any of the preceding embodiments A1 toA115, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 70 (peptide 099) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 253 (peptide 012), 264(peptide 26B), 82 (peptide 110) or 269 (peptide 125), or a variantsequence thereof, a derivative thereof or a salt thereof.

Embodiment A117

The composition according to any of the preceding embodiments A1 toA116, wherein the peptide consisting of an amino acid sequence of SEQ IDNO: 52 (peptide 081) is replaced by a substitute peptide consisting ofan amino acid sequence selected from SEQ ID NOS: 250 (peptide 009), 254(peptide 022), 10 (peptide 042), 18 (peptide 050), 258 (peptide 122), 23(peptide 055), 128, 129, 272, 187, 188 or 273, or a variant sequencethereof, a derivative thereof or a salt thereof.

Embodiment A118

The composition according to any of the preceding embodiments A1 toA117, wherein the peptide combination comprises at least one peptideconsisting of an amino acid sequence derived from allergen Der p 1, or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A119

The composition according to any of the preceding embodiments A1 toA118, wherein the peptide combination comprises at least one peptideconsisting of an amino acid sequence derived allergen Der p 2, or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A120

The composition according to any of the preceding embodiments A1 toA119, wherein the peptide combination comprises at least one peptideconsisting of an amino acid sequence derived from allergen Der f 1, or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A121

The composition according to any of the preceding embodiments A1 toA120, wherein the peptide combination comprises at least one peptideconsisting of an amino acid sequence derived from allergen Der f 2, or avariant sequence thereof, a derivative thereof or a salt thereof.

Embodiment A122

The composition according to any of embodiments A119 to A122, whereinthe peptide combination comprises at least one peptide derived from eachof the allergens Der p 1 and Der p 2.

Embodiment A123

The composition according to any of embodiments A119 to A122, whereinthe peptide combination comprises at least one peptide derived from eachof the allergens Der p 1 and Der f 2.

Embodiment A124

The composition according to any of embodiments A119 to A122, whereinthe peptide combination comprises at least one peptide derived from eachof the allergens Der p 1, Der p 2, Der f 1 and Der f 2.

Embodiment A125

The composition according to any of the preceding embodiments A1 toA124, wherein the allergens Der p 1, Der p 2, Der f 1 and Der f 2,respectively, consist of the amino acid sequences set out in Table 1.

Embodiment A126

The composition according to any of the preceding embodiments A1 toA125, wherein the peptide combination comprises 3, 4, 5, 6, 7, 8, 9 or10 or more peptides, preferably no more than 5, 6 or 7 peptides.

Embodiment A127

The composition according to any of the preceding embodiments A1 toA126, wherein a variant sequence thereof comprises additional amino acidresidues at the N- and/or C-terminal end.

Embodiment A128

The composition according to embodiment A127, wherein the additionalamino acids are selected from amino acids flanking the N- and/orC-terminal ends when the peptide is aligned with the allergen it ispresent in, based upon or derived from.

Embodiment A129

The composition according to embodiment A128, wherein the allergen isselected from an allergen set out in Table 1, for example the allergensDerp1.0105 or an isoform thereof, Derf1.0101 or an isoform thereof,Derp2.0101 or an isoform thereof, Derf2.0103 or an isoform thereof.

Embodiment A130

The composition according to any of the preceding embodiments A1 toA129, wherein the variant sequence of a peptide is a longer peptide ofup to 60 amino acids in length, which longer peptide comprises an aminoacid sequence having at least 65% identity or homology over the lengthof the amino acid sequence of the peptide

Embodiment A131

The composition according to any of the preceding embodiments A1 toA130, wherein the variant sequence of peptide is a longer peptide of upto 60, 55, 50, 45, 40, 35, 30, 28, 25, 24, or 22 amino acids in length,which longer peptide comprises an amino acid sequence having at least65%, 70%, 75%, 80%, 85%, 90%, 95% identity or homology over the lengthof the amino acid sequence of the peptide.

Embodiment A132

The composition according to any of the embodiments A131 and A132,wherein the variant sequence of a peptide is a longer peptide of up to30 amino acids in length, which longer peptide comprises an amino acidsequence having at least 80% identity or homology over the length of theamino acid sequence of the peptide.

Embodiment A133

The composition according to any of the preceding embodiments A1 toA132, wherein the variant sequence of a peptide is a fragment of thepeptide comprising at least 15 amino acids in length, which fragment hasat least 65% identity or homology over the length of the fragment whenaligned with the peptide.

Embodiment A134

The composition according to any of the preceding embodiments A1 toA133, wherein the variant sequence is a fragment of the peptidecomprising at least 15, such as at least 16, 17 or 18, amino acids inlength with at least 65%, such as at least 70%, 75%, 80%, 85%, 90%, 95%,identity or homology over the length of the fragment when aligned withthe peptide.

Embodiment A135

The composition according to any of embodiments A134 and A135, whereinthe fragment consist of or comprises an amino sequence selected from SEQID NOS: 90, 102, 161, 103, 105, 106, 111, 114, 115, 173, 174, 117, 176,120, 121, 180, 128, 187, 188, 191, 133, 192, 199, 226, 227, 205, 229,206, 230, 208, 233, 210, 234, 242, 243, 221, 245, 246, 283, 223, 247,224, 248, or a variant sequence, a derivative or a salt thereof

Embodiment A136

The composition according to any of the preceding embodiments A1 toA135, wherein the variant sequence thereof has at least 65% identity orhomology over at least 15 contiguous amino acids of the peptide.

Embodiment A137

The composition according to any of the preceding embodiments A1 toA136, wherein the variant sequence thereof has at least 65%, such as atleast 70%, 75%, 80%, 85%, 90%, 95% identity or homology over at least15, such as over at least 16, 17, 18, 19, 20 contiguous amino acids ofthe peptide.

Embodiment A138

The composition according to any of the preceding embodiments A1 toA137, wherein a variant sequence thereof comprises a glutamate residuepresent at the N-terminus of a peptide replaced with pyroglutamate.

Embodiment A139

The composition according to any of the preceding embodiments A1 toA138, wherein a variant sequence thereof comprises the addition of oneor more lysine amino residue(s) or arginine amino acid residue(s) at theN- or C-terminus of the peptide.

Embodiment A140

The composition according to any one of the preceding embodiments A1 toA139, wherein a variant sequence thereof comprises one or moremodifications selected from the following: (a) any cysteine residues inthe native sequence of the peptide are replaced with serine or2-aminobutyric acid; (b) hydrophobic residues in the up to three aminoacids at the N or C terminus of the native sequence of the peptide aredeleted; (c) any two consecutive amino acids comprising the sequenceAsp-Gly in the up to four amino acids at the N or C terminus of thenative sequence of the peptide are deleted; and/or (d) one or morepositively charged residues are added at the N- and/or C-terminus

Embodiment A141

The composition according to any one of the preceding embodiments A1 toA140, wherein a derivative thereof comprises one or more modificationsselected from the following: (a) N terminal acetylation; (b) C terminalamidation; (c) one or more hydrogens on the side chain amines ofArginine and/or Lysine replaced with a methylene group; (d)glycosylation and/or (e) phosphorylation.

Embodiment A142

The composition according to any one of the preceding embodiments A1 toA141, wherein the salt is a pharmaceutically acceptable and/or aphysiologically acceptable salt.

Embodiment A143

The composition according to any one of the preceding embodiments A1 toA142 wherein the salt is an acid addition salt with an inorganic acid,acid addition salt with an organic acid, salt with a basic inorganicacid, salt with a basis organic acid, salt with an acidic or basic aminoacid or a mixture thereof,

Embodiment A144

The composition according to embodiment A144, wherein an acid additionsalt with an inorganic acid is selected from salts with hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, orthe like.

Embodiment A145

The composition according to embodiment A144, wherein an acid salt withan organic acids is selected from salts with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, or the like.

Embodiment A146

The composition according to embodiment A144, wherein a salt with aninorganic base is selected from a salt of an alkali metal salts such assodium salts and potassium salts; alkali earth metal salts such ascalcium salts and magnesium salts; and aluminum salts and ammoniumsalts;

Embodiment A147

The composition according to embodiment A144, wherein a salt with abasic organic bases is selected from any salt with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine,caffeine, piperidine, and pyridine;

Embodiment A148

The composition according to embodiment A144, wherein a salt with abasic amino acid is selected from any salt with arginine, lysine,ornithine, or the like:

Embodiment A149

The composition according to embodiment A144, wherein a salt with anacidic amino acid is selected from any salt with aspartic acid, glutamicacid, or the like.

Embodiment A150

The composition according to embodiment A144, wherein a salt thereof isan acetate salt.

Embodiment A151

The composition according to any one of the preceding embodiments A1 toA150, wherein the peptides are synthetically made.

Embodiment A152

The composition according to any one of the preceding embodiments A1 toA151, wherein the peptides are freeze-dried.

Embodiment A153

The composition according to any one of the preceding embodiments A1 toA152, wherein each peptide is present in equimolar concentrations or insubstantially equimolar concentrations.

Embodiment A154

The composition according to any one of the preceding embodiments A1 toA153, wherein each peptide is present in a molar concentration 1 to 1000μM, for example in the range of 10 to 800 μM, for example in the rangeof 20 to 500 μM, for example in the range of 20 to 300 μM.

Embodiment A155

A pharmaceutical composition comprising a composition according to anyof embodiments A1 to A154.

Embodiment A156

The pharmaceutical composition according to embodiment A155, furthercomprising a pharmaceutically acceptable carrier, excipient and/oradjuvant, optionally sterile.

Embodiment A157

The pharmaceutical composition according to any of embodiments A155 andA156 formulated as a vaccine, optionally sterile.

Embodiment A158

The pharmaceutical composition according to any of embodiments A155 toA157, wherein the pharmaceutical composition is a powder, for example infreeze-dried form, optionally sterile.

Embodiment A159

The pharmaceutical composition according to any of embodiments A155 toA158, wherein the composition is adapted to be re-dissolved before use,for example in an aqueous, optionally sterile, solution, for example asolution having a pH in the range of 3 to 9, such as pH of 3 to 8, suchas pH of 4 to 8.

Embodiment A160

The pharmaceutical composition according to any of embodiments A155 toA159, wherein the composition comprises saline, optionally sterile, andoptionally further comprising a pH controlling or buffering agent, awetting agent, a dispersant, a thickener or a preservative oranti-microbial agent.

Embodiment A161

A kit comprising a compartment and instructions, wherein the compartmentcomprises one or more of the compositions of any one of embodiments A1to A160 and wherein the instructions are for use in treating allergy todust mites, such as house dust mites.

Embodiment A162

The kit of embodiment A161, wherein the kit further comprises packagingmaterial comprising corrugated fiber, glass, plastic, foil, ampules,vials, blister pack, preloaded syringes or tubes, optionally thatmaintains sterility of the components.

Embodiment A163

The kit of embodiment A161 or A162, wherein the kit further compriseslabels or inserts comprising printed matter or computer readable mediumoptionally including identifying components, dose amounts, clinicalpharmacology, instructions for the clinician or for a subject using oneor more of the kit components, prophylactic or therapeutic benefits,adverse side effects or manufacturer information.

Embodiment A164

A method for treating allergy to dust mites, such as house dust mites,in a subject in need thereof, comprising administering a therapeuticallysufficient amount of a composition according to any of embodiments A1 toA160.

Embodiment A165

A composition according to any of embodiments A1 to A160 for use in thetreatment of allergy to dust mites, such as house dust mites in asubject in need thereof.

Embodiment A166

Use of a composition according to any of embodiments A1 to A160 for thepreparation of a medicament for the treatment of allergy to dust mites,such as house dust mites, in a subject in need thereof.

Embodiment A167

The method and uses according to any of embodiments A164 to A166,wherein the treatment of allergy to dust mite, such as to a house dustmite, is by immunotherapy.

Embodiment A168

The method and uses according to any of embodiments A164-A167, whereinthe house dust mite allergy is clinically presented as atopicdermatitis, urticaria, contact dermatitis, allergic conjunctivitis,allergic rhinitis, allergic asthma, anapylaxis, and/or hay fever.

Embodiment A169

The method and uses according to embodiments any of A164-A167, whereinthe method or use decreases, reduces, suppresses or inhibits atopicdermatitis, urticaria, contact dermatitis, allergic conjunctivitis,allergic rhinitis, allergic asthma, anaphylaxis, and/or hay fever.

Embodiment A170

The method and uses according to any of embodiments A164-A167, whereinthe method or use comprises modulating, decreasing, reducing,suppressing or inhibiting a T cell or antibody response.

Embodiment A171

The method and uses according to embodiment A170, wherein the T cellresponse is an IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13,IL17, IL-22, IL-31 or IFN-g response.

Embodiment A172

The method and uses according to any of embodiments A164 to A171,wherein the method or use comprises the repeated administration of thecomposition (peptide combination).

Embodiment A173

The method and uses according to any of embodiments A164 to A172,wherein the administration is by a route of administration selected fromsubcutaneous, intradermal, epicutaneous, rectal, topical, sublingual,oral, buccal, intranasal, respiratory and intralymphatic route.

Embodiment A174

The method and uses according to any of embodiments A164 to A173,wherein the subject in need thereof is a human, a pet such as a dog or acat or a domestic animal such as a horse.

Embodiment A175

The method and uses according to any of embodiments A164 to A174,wherein the house dust mite is of the genus Dermatophagoides, such as ofthe species Dermatophagoides farinae and/or Dermatophagoidespteronyssinus.

Embodiment A176

The method and uses according to any of embodiments A164 to A175,wherein the treatment of allergy to a dust mite is for the treatment ofallergy to a dust mite allergen, such as to a house dust mite allergen,for example allergens Der p 1, Der p 2, Der f 1 and/or Der f 2, oranother allergen of the genus Dermatophagoides (e.g. Der p 4) or anotherallergen of the species Dermatophagoides farinae and/or Dermatophagoidespteronyssinus.

Embodiment A177

The method and uses according to any of embodiments A164 to A176,wherein the subject in need thereof has specific IgE antibodies againstDer p 1, Der p 2, Der f 1 and/or Der f 2.

Embodiment A178

The method and uses according to any of embodiments A164 to A177,wherein the subject in need thereof has a T cell response to thecomposition, such as to the peptide combination or single peptidesthereof.

Embodiment A179

The method and uses according to any of embodiments A164 to A178,wherein a single dose of each single peptide of the composition is inthe range of 1 to 1000 nanomole, for example in the range of 1 to 500nanomole, for example in the range of 5 to 250 nanomole.

Embodiment A180

The method and uses according to any of embodiments A164 to A179,wherein an amount of about 50 to 150 microliter is administered, such asby intradermal administration.

Embodiment A181

An in vitro method of determining whether T cells of a subject in needof treatment recognize a composition as defined in any one ofembodiments A1 to A160 comprising contacting said T cells obtained fromthe subject in need thereof with said peptide combination or singlepeptides thereof and detecting whether said T cells are stimulated bysaid peptide.

Embodiment A182

The method according to embodiment A181, which is carried out todetermine whether a subject has, or is at risk of developing, an allergyto dust mite allergy.

Embodiment A183

The method and uses according to any of the preceding embodiments A1 toA182, wherein a T cell is a helper T cell, such as a Th2 cell.

LIST OF REFERENCES

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Examples Example 1 House Dust Mite Peptide Library

This example includes a description of the peptide library used to mapT-cell epitopes of major house dust mite allergens.

A complete set of overlapping 20mer peptides deriving from the fulllength amino acid sequences of allergens proDer p 1, proDer f 1, Der p 2and Der f 2, were purchased from Thermo Scientific Custom Biopolymers,Germany having a purity of >95%. For the present study the followingisoforms of the allergens were used for peptide design: Der p 1.0105(variant of UniProt number P08176), Der f 1.0101 (UniProt numberQ58A71), Der p 2.0101 (UniProt number P49278) and Der f 2.0103 (variantof UniProt number Q00855). These isoforms were confirmed to be abundantisoforms in house dust mite extracts by mass spectrometry (LC-MS/MS),but alternatively other isoforms of these allergens could have been used(see www.allergen.org for a complete and updated list of isoforms).Examples of isoforms of Der p 1, Der f 1, Der p 2 and Der f 2 are shownin Table 1. To avoid dimerization and polymerization of peptides byintra- and intermolecular disulfide bond formation between cysteineresidues, this amino acid was consistently substituted by a serineresidue in the set of overlapping 20mer peptides. The set of 20merpeptides is shown in Tables 2 and 3.

A complete set of overlapping 15mer peptides deriving from the sameisoforms of proDer p 1, proDer f 1, Der p 2 and Der f 2 was purchasedfrom A and A (San Diego, Calif.) as crude material on a small (1 mg)scale. Cysteine residues were not substituted by a serine in the set of15mers peptide library. The set of 15mer peptides is shown in Tables 4and 5.

Additional peptides were added to the peptide library by selecting housedust mite allergen group 1 or group 2 peptides previously shown in theart to induce T cell activation in house dust mite allergic donorpopulation. The additional peptides were selected based on their broadHLA Class II allele coverage. Table 6 shows ten additional peptides (SEQID NOs: 249-258) together with 7 peptides (SEQ ID NOs: 259-265)previously suggested for a peptide combination for treating house dustmite allergy (International patent application WO2009 022156).

TABLE 1 Sequences of isoforms of house dust mite allergens Der p 1,Der f 1, Der p 2 and Der f 2. SEQ ID NO: Table 1 287 >Derp1.0101RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAHRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAANIDLMMIEEYPYVVIL 288 >Derp1.0102RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL289 >Derp1.0103RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIKYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL290 >Derp1.0104RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAHRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHTAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEQYPYVVIL291 >Derp1.0105RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL292 >Derp1.0106RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQHDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL293 >Derp1.0107RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNAN KIREALAQTHTAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL294 >Derp1.0108RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL295 >Derp1.0109RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRPVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL296 >Derp1.0110RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATDSAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL297 >Derp1.0111RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNASKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEKYPYVVIL298 >Derp1.0112RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIRKALAQTHSAMAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEKYPYVVIL299 >Derp1.0113RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQIRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNASKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEGYPYVVIL300 >Derp1.0114RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIAYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL301 >Derp1.0115RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRWTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNTQRFGISNYSQTYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL302 >Derp1.0116RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYYAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL303 >Derp1.0117RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNAN KIREALTQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL304 >Derp1.0118RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQIRIVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL305 >Derp1.0119RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIGYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL306 >Derp1.0120RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNAN KIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIRRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL307 >Derp1.0121RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRSQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNVNKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEGYPYVVIL308 >Derp1.0122RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGTSNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL309 >Derp1.0123RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEGYPYVVIL310 >Derp1.0124RPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNQSLDLAEQELVDSASQHGSNGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL311 >Derp1.0105rRPSSIKTFEEYKKAFQKSYATFEDEEAARKNFLESVKYVQSNGGAINHLSDLSLDEFKNRFLMSAEAFEHLKTQFDLNAETNASSINGNAPAEIDLRQMRTVTPIRMQGGSGSSWAFSGVAATESAYLAYREQSLDLAEQELVDSASQHGSHGDTIPRGIEYIQHNGVVQESYYRYVAREQSSRRPNAQRFGISNYSQIYPPNANKIREALAQTHSAIAVIIGIKDLDAFRHYDGRTIIQRDNGYQPNYHAVNIVGYSNAQGVDYWIVRNSWDTNWGDNGYGYFAA NIDLMMIEEYPYVVIL312 >Derf1.0101RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM313 >Derf1.0102RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQRDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM314 >Derf1.0103RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYGGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM315 >Derf1.0104RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAEISASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGRHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAGN NLMMIEQYPYVVIM316 >Derf1.0105RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYDISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM317 >Derf1.0106RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQRSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGDDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM318 >Derf1.0107RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQRSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM319 >Derf1.0108RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTATPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM320 >Derf1.0109RPASIKTFEEFKKAFNKNYAIVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQKLVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM321 >Derf1.0110RPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRNTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQQSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIRHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM322 >Derf1.0107rRPASIKTFEEFKKAFNKNYATVEEEEVARKNFLESLKYVEANKGAINHLSDLSLDEFKNRYLMSAEAFEQLKTQFDLNAETSASRINSVNVPSELDLRSLRTVTPIRMQGGSGSSWAFSGVAATESAYLAYRQTSLDLSEQELVDSASQHGSHGDTIPRGIEYIQQNGVVEERSYPYVAREQRSRRPNSQHYGISNYSQIYPPDVKQIREALTQTHTAIAVIIGIKDLRAFQHYDGRTIIQHDNGYQPNYHAVNIVGYGSTQGVDYWIVRNSWDTTWGDSGYGYFQAG NNLMMIEQYPYVVIM323 >Derp2.0101DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNTKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDD GVLASAIATHAKIRD324 >Derp2.0102DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDN GVLASAIATHAKLRD325 >Derp2.0103DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEALFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVIVKVMGDN GVLASAIATHAKIRD326 >Derp2.0104DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEALFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVLGDNG VLASAIATHAKIRD327 >Derp2.0105DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEALFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVIVKVMGDD GVLASAIATHAKIRD328 >Derp2.0106DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNTKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKITPKSENVVVTVKVMGDD GVLASAIATHAKIRD329 >Derp2.0107DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDD GVLASAIATHAKIRD330 >Derp2.0108DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDD GALASAIATHAKIRD331 >Derp2.0109DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVLGDNG VLASAIATHAKIRD332 >Derp2.0110DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVLGDNG VLASAIATHAKIRD333 >Derp2.0111DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEALFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDN GVLASAIATHAKIRD334 >Derp2.0112DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNTKTAKIEIKASIDGLEVDVPGIDPNASHYVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVIVKVIGDNG VLASAIATHAKIRD335 >Derp2.0113DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNTKNAKIEIKASIDGLEVDVPGIDPNASHYVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDN GVLASAIATHAKIRD336 >Derp2.0114DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEALFEANQNTKNAKIEIKASIDGLEVDVPGIDPNASHYVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVIVKVLGDNG VLASAIATHAKIRD337 >Derp2.0115DQVDVKDSANHEIKKVLVPGSHGSEPSIIHRGKPFQLEAVFEANQNSKTAKIEIKASIDGLEVDVPGIDPNASHYMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKVMGDN GVLASAIATHAKIRD338 >Derf2.0101DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKASLDGLEIDVPGIDTNASHFVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKLIGDNGV LASAIATHGKIRD339 >Derf2.0102DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKASLDGLEIDVPGIDTNASHFMKSPLVKGQQYDIKYTWNVPKIAPKSENVVVIVKLIGDNG VLASAIATHGKIRD340 >Derf2.0103DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKASLDGLEIDVPGIDTNASHFMKSPLVKGQQYDAKYTWNVPKIAPKSENVVVIVKLVGDNG VLASAIATHAKIRD341 >Derf2.0104DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKTEIKASLDGLEIDVPGIDTNASHFMKSPLVKGQQYDAKYTWNVPKIAPKSENVVVTVKLVGDNGVLASAIATHAKIRD 342 >Derf2.0105DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKASLDGLEIDVPGIDTNASHFMKSPLVKGQQYDAKYTWNVPKIAPESENVVVIVKLVGDNG VLASAIATHAKIRD343 >Derf2.0106DQVDVKDSANHEIKKVMVDGSHGSDPSIIHRGKPFNLEAIFDANQNTKTAKIEIKANIDGLEVDVPGIDTNASHYIKSPLVKGQQYDAKYTWNVPKIAPKSENVVVIVKLVGDNG VLASAIATHAKIRD344 >Derf2.0107DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHYIKSPLVKGQQYDAKYTWNVPKIAPKSENVVVIVKLIGDNG VLASAIATHAKIRD345 >Derf2.0108DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANIDGLEVDVPGIDTNASHYIKSPLVKGQQYDAKYTWNVPKIAPKSENVVVIVKLVGDNG VLASAIATHAKIRD346 >Derf2.0109DQVDVKDSANNEIKKVMVDGRHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHFVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVIVKLIGDNG VLASAIATHAKIRD347 >Derf2.0110DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEADVPGIDTNASHYIKSPLVKGQQYDAKYTWNVPKIAPKSENVVVIVKLIGDNG VLASAIATHAKIRD348 >Derf2.0111DQVDVKDSANNEIKKVMVDGRHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHFVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKLIGDNG VLASAIATHAKIRD349 >Derf2.0112DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKASLDGLEIDVPGIDTNASHFMKSPLVKGQQYDAKYTWNVPKIAPKSENVVVIVKLVGDNG VLASAIATHGKIRD350 >Derf2.0113DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKASLDGLETDVPGIDTNASHFMKSPLVKGQQYDAKYTWNVPKIAPKSENVVVTVKLIGDNG VLASAIATHGKIRD351 >Derf2.0114DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHFVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKLIGDNG VLASAIATHGKIRD352 >Derf2.0115DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHFVKSPLVKGQQYDIKYTWNVPKIAPKSENVVVTVKLIGDNG VLASAIATHGKISD353 >Derf2.0116DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHYIKSPLVKGQQYDAKYTWNVPKIAPKSENVVVTVKLIGDNG VLASAIATHGKIRD354 >Derf2.0117DQVDVKDSANNEIKKVMVDGSHGSDPSIIHRGKPFTLEALFDANQNTKTAKIEIKANINGLEVDVPGIDTNASHYIKSPLVKGQQYDIKYTWNVPKIAPKSENVVV1VKLIGDNGV LASAIATHGKIRD

TABLE 2 Peptide library of Der p 1 and Der f 1 (20 mers peptides) SEQSequence SEQ Sequence ID Pep Start derived from ID Pep Startderived from NO: No pos Der p 1 NO: No pos Der f 1 Pro-protein 1 33 1RPSSIKTFEEYKKAFNKSYA 30 62 1 RPASIKTFEEFKKAFNKNYA 2 34 11YKKAFNKSYATFEDEEAARK 31 63 11 FKKAFNKNYATVEEEEVARK 3 35 21TFEDEEAARKNFLESVKYVQ 32 64 21 TVEEEEVARKNFLESLKYVE 4 36 31NFLESVKYVQSNGGAINHLS 33 65 31 NFLESLKYVEANKGAINHLS 5 37 41SNGGAINHLSDLSLDEFKNR 34 66 41 ANKGAINHLSDLSLDEFKNR 6 38 51DLSLDEFKNRFLMSAEAFEH 35 67 51 DLSLDEFKNRYLMSAEAFEQ 7 39 61FLMSAEAFEHLKTQFDLNAE 36 68 61 YLMSAEAFEQLKTQFDLNAE 8 40 71LKTQFDLNAETNASSINGN 37 69 71 LKTQFDLNAETSASRINSVN Mature protein 9 41 81TNASSINGNAPAEIDLRQM 38 70 81 TSASRINSVNVPSELDLRSL 10 42 90APAEIDLRQMRTVTPIRMQG 39 71 91 VPSELDLRSLRTVTPIRMQG 11 43 100RTVTPIRMQGGSGSSWAFSG 40 43 101 RTVTPIRMQGGSGSSWAFSG 12 44 110GSGSSWAFSGVAATESAYLA 41 44 111 GSGSSWAFSGVAATESAYLA 13 45 120VAATESAYLAYRNQSLDLAE 42 72 121 VAATESAYLAYRNTSLDLSE 14 46 130YRNQSLDLAEQELVDSASQH 43 73 131 YRNTSLDLSEQELVDSASQH 15 47 140QELVDSASQHGSHGDTIPRG 44 47 141 QELVDSASQHGSHGDTIPRG 16 48 150GSHGDTIPRGIEYIQHNGVV 45 74 151 GSHGDTIPRGIEYIQQNGVV 17 49 160IEYIQHNGVVQESYYRYVAR 46 75 161 IEYIQQNGVVEERSYPYVAR 18 50 170QESYYRYVAREQSSRRPNAQ 47 76 171 EERSYPYVAREQQSRRPNSQ 19 51 180EQSSRRPNAQRFGISNYSQI 48 77 181 EQQSRRPNSQHYGISNYSQI 20 52 190RFGISNYSQIYPPNANKIRE 49 78 191 HYGISNYSQIYPPDVKQIRE 21 53 200YPPNANKIREALAQTHSAIA 50 79 201 YPPDVKQIREALTQTHTAIA 22 54 210ALAQTHSAIAVIIGIKDLDA 51 80 211 ALTQTHTAIAVIIGIKDLRA 23 55 220VIIGIKDLDAFRHYDGRTII 52 81 221 VIIGIKDLRAFQHYDGRTII 24 56 230FRHYDGRTIIQRDNGYQPNY 53 82 231 FQHYDGRTIIQHDNGYQPNY 25 57 240QRDNGYQPNYHAVNIVGYSN 54 83 241 QHDNGYQPNYHAVNIVGYGS 26 58 250HAVNIVGYSNAQGVDYWIVR 55 84 251 HAVNIVGYGSTQGVDYWIVR 27 59 260AQGVDYWIVRNSWDTNWGDN 56 85 261 TQGVDYWIVRNSWDTTWGDS 28 60 270NSWDTNWGDNGYGYFAANID 57 86 271 NSWDTTWGDSGYGYFQAGNN 29 61 280GYGYFAANIDLMMIEEYPYVVIL 58 87 281 GYGYFQAGNNLMMIEQYPYVVIM

Table 2 shows overlapping 20mers peptides of allergen Der p 1 (isoform1.0105) and allergen Der f 1 (isoform 1.0101). Underlined amino acid Sindicates that a cysteine residue is replaced with serine)

TABLE 3 Peptide library of Der p 2 and Der f 2 (20 mers peptides) SEQSequence SEQ Sequence ID Pep Start derived from ID Pep Startderived from NO: No pos Der p 2 NO: No pos Der f 2 59 88 1DQVDVKDSANHEIKKVLVP 71 100 1 DQVDVKDSANNEIKKVMVD 60 89 10NHEIKKVLVPGSHGSEPSII 72 101 10 NNEIKKVMVDGSHGSDPSII 61 90 20GSHGSEPSIIHRGKPFQLEA 73 102 20 GSHGSDPSIIHRGKPFTLEA 62 91 30HRGKPFQLEAVFEANQNTKT 74 103 30 HRGKPFTLEALFDANQNTK 63 92 40VFEANQNTKTAKIEIKASID 75 104 40 LFDANQNTKTAKIEIKASLD 64 93 50AKIEIKASIDGLEVDVPGID 76 105 50 AKIEIKASLDGLEIDVPGID 65 94 60GLEVDVPGIDPNASHYMKSP 77 106 60 GLEIDVPGIDTNASHFMKSP 66 95 70PNASHYMKSPLVKGQQYDIK 78 107 70 TNASHFMKSPLVKGQQYDAK 67 96 80LVKGQQYDIKYTWNVPKIAP 79 108 80 LVKGQQYDAKYTWNVPKIAP 68 97 90YTWNVPKIAPKSENVVVTVK 80 97 90 YTWNVPKIAPKSENVVVTVK 69 98 100KSENVVVTVKVMGDDGVLAS 81 109 100 KSENVVVTVKLVGDNGVLAS 70 99 110VMGDDGVLASAIATHAKIRD 82 110 110 LVGDNGVLASAIATHAKIRD

Table 3 shows overlapping 20mers peptides of Der p 2 (isoform 2.0101)and Der f 2 (isoform 2.0103)

TABLE 4 Peptide library of Der p 1 and Der f 1 (15 mers peptides)Sequence Sequence SEQ ID Start derived from SEQ ID Start derived fromNO: pos Der p 1 NO: pos Der f 1 83 1 RPSSIKTFEEYKKAF 142 1RPASIKTFEEFKKAF 84 6 KTFEEYKKAFNKSYA 143 6 KTFEEFKKAFNKNYA 85 11YKKAFNKSYATFEDE 144 11 FKKAFNKNYATVEEE 86 16 NKSYATFEDEEAARK 145 16NKNYATVEEEEVARK 87 21 TFEDEEAARKNFLES 146 21 TVEEEEVARKNFLES 88 26EAARKNFLESVKYVQ 147 26 EVARKNFLESLKYVE 89 31 NFLESVKYVQSNGGA 148 31NFLESLKYVEANKGA 90 36 VKYVQSNGGAINHLS 149 36 LKYVEANKGAINHLS 91 41SNGGAINHLSDLSLD 150 41 ANKGAINHLSDLSLD 92 46 INHLSDLSLDEFKNR 151 46INHLSDLSLDEFKNR 93 51 DLSLDEFKNRFLMSA 152 51 DLSLDEFKNRYLMSA 94 56EFKNRFLMSAEAFEH 153 56 EFKNRYLMSAEAFEQ 95 61 FLMSAEAFEHLKTQF 154 61YLMSAEAFEQLKTQF 96 66 EAFEHLKTQFDLNAE 155 66 EAFEQLKTQFDLNAE 97 71LKTQFDLNAETNACS 156 71 LKTQFDLNAETSACR 98 76 DLNAETNACSINGNA 157 76DLNAETSACRINSVN 99 81 TNACSINGNAPAEI 158 81 TSACRINSVNVPSEL 100 86INGNAPAEIDLRQM 159 86 INSVNVPSELDLRSL 101 91 PAEIDLRQMRTVTP 160 91VPSELDLRSLRTVTP 102 96 DLRQMRTVTPIRMQG 161 96 DLRSLRTVTPIRMQG 103 101RTVTPIRMQGGCGSC 162 101 RTVTPIRMQGGCGSC 104 106 IRMQGGCGSCWAFSG 163 106IRMQGGCGSCWAFSG 105 111 GCGSCWAFSGVAATE 164 111 GCGSCWAFSGVAATE 106 116WAFSGVAATESAYLA 165 116 WAFSGVAATESAYLA 107 121 VAATESAYLAYRNQS 166 121VAATESAYLAYRNTS 108 126 SAYLAYRNQSLDLAE 167 126 SAYLAYRNTSLDLSE 109 131YRNQSLDLAEQELVD 168 131 YRNTSLDLSEQELVD 110 136 LDLAEQELVDCASQH 169 136LDLSEQELVDCASQH 111 141 QELVDCASQHGCHGD 170 141 QELVDCASQHGCHGD 112 146CASQHGCHGDTIPRG 171 146 CASQHGCHGDTIPRG 113 151 GCHGDTIPRGIEYIQ 172 151GCHGDTIPRGIEYIQ 114 156 TIPRGIEYIQHNGVV 173 156 TIPRGIEYIQQNGVV 115 161IEYIQHNGVVQESYY 174 161 IEYIQQNGVVEERSY 116 166 HNGVVQESYYRYVAR 175 166QNGVVEERSYPYVAR 117 171 QESYYRYVAREQSCR 176 171 EERSYPYVAREQQCR 118 176RYVAREQSCRRPNAQ 177 176 PYVAREQQCRRPNSQ 119 181 EQSCRRPNAQRFGIS 178 181EQQCRRPNSQHYGIS 120 186 RPNAQRFGISNYCQI 179 186 RPNSQHYGISNYCQI 121 191RFGISNYCQIYPPNA 180 191 HYGISNYCQIYPPDV 122 196 NYCQIYPPNANKIRE 181 196NYCQIYPPDVKQIRE 123 201 YPPNANKIREALAQT 182 201 YPPDVKQIREALTQT 124 206NKIREALAQTHSAIA 183 206 KQIREALTQTHTAIA 125 211 ALAQTHSAIAVIIGI 184 211ALTQTHTAIAVIIGI 126 216 HSAIAVIIGIKDLDA 185 216 HTAIAVIIGIKDLRA 127 221VIIGIKDLDAFRHYD 186 221 VIIGIKDLRAFQHYD 128 226 KDLDAFRHYDGRTII 187 226KDLRAFQHYDGRTII 129 231 FRHYDGRTIIQRDNG 188 231 FQHYDGRTIIQHDNG 130 236GRTIIQRDNGYQPNY 189 236 GRTIIQHDNGYQPNY 131 241 QRDNGYQPNYHAVNI 190 241QHDNGYQPNYHAVNI 132 246 YQPNYHAVNIVGYSN 191 246 YQPNYHAVNIVGYGS 133 251HAVNIVGYSNAQGVD 192 251 HAVNIVGYGSTQGVD 134 256 VGYSNAQGVDYWIVR 193 256VGYGSTQGVDYWIVR 135 261 AQGVDYWIVRNSWDT 194 261 TQGVDYWIVRNSWDT 136 266YWIVRNSWDTNWGDN 195 266 YWIVRNSWDTTWGDS 137 271 NSWDTNWGDNGYGYF 196 271NSWDTTWGDSGYGYF 138 276 NWGDNGYGYFAANID 197 276 TWGDSGYGYFQAGNN 139 281GYGYFAANIDLMMIE 198 281 GYGYFQAGNNLMMIE 140 286 AANIDLMMIEEYPYV 199 286QAGNNLMMIEQYPYV 141 289 IDLMMIEEYPYVVIL 200 289 NNLMMIEQYPYVVIM

Table 4 shows overlapping 15mers peptides of Der p 1 (isoform 1.0105)and Der f 1 (isoform 1.0101)

TABLE 5 Peptide library of Der p 2 and Der f 2 (15 mers peptides)Sequence Sequence SEQ ID Start derived from SEQ ID Start derived fromNO: pos Der p 2 NO: pos Der f 2 201 1 DQVDVKDCANHEIKK 225 1DQVDVKDCANNEIKK 202 6 KDCANHEIKKVLVPG 226 6 KDCANNEIKKVMVDG 203 11HEIKKVLVPGCHGSE 227 11 NEIKKVMVDGCHGSD 204 16 VLVPGCHGSEPCIIH 228 16VMVDGCHGSDPCIIH 205 21 CHGSEPCIIHRGKPF 229 21 CHGSDPCIIHRGKPF 206 26PCIIHRGKPFQLEAV 230 26 PCIIHRGKPFTLEAL 207 31 RGKPFQLEAVFEANQ 231 31RGKPFTLEALFDANQ 208 36 QLEAVFEANQNTKTA 232 36 TLEALFDANQNTKTA 209 41FEANQNTKTAKIEIK 233 41 FDANQNTKTAKIEIK 210 46 NTKTAKIEIKASIDG 234 46NTKTAKIEIKASLDG 211 51 KIEIKASIDGLEVDV 235 51 KIEIKASLDGLEIDV 212 56ASIDGLEVDVPGIDP 236 56 ASLDGLEIDVPGIDT 213 61 LEVDVPGIDPNACHY 237 61LEIDVPGIDTNACHF 214 66 PGIDPNACHYMKCPL 238 66 PGIDTNACHFMKCPL 215 71NACHYMKCPLVKGQQ 239 71 NACHFMKCPLVKGQQ 216 76 MKCPLVKGQQYDIKY 240 76MKCPLVKGQQYDAKY 217 81 VKGQQYDIKYTWNVP 241 81 VKGQQYDAKYTWNVP 218 86YDIKYTWNVPKIAPK 242 86 YDAKYTWNVPKIAPK 219 91 TWNVPKIAPKSENVV 243 91TWNVPKIAPKSENVV 220 96 KIAPKSENVVVTVKV 244 96 KIAPKSENVVVTVKL 221 101SENVVVTVKVMGDDG 245 101 SENVVVTVKLVGDNG 222 106 VTVKVMGDDGVLACA 246 106VTVKLVGDNGVLACA 223 111 MGDDGVLACAIATHA 247 111 VGDNGVLACAIATHA 224 115GVLACAIATHAKIRD 248 115 GVLACAIATHAKIRD

Table 5 shows overlapping 15mers peptides of Der p 2 (isoform 2.0101)and Der f 2 (isoform 2.0103)

TABLE 6 Additional Peptide Library SEQ ID Peptide Position NO: ID NoSpecies Start Sequence 249 002 Der p 2  26 SIIHRGKPFQLEA 250 009 Der p 1 24 ESAYLAYRNQSLDLAE 251 010 Der p 1 277 DNGYGYFAANIDLMMIEE 252 011Der p 1 278 NGYGYFAANIDLMM 253 012 Der p 2 115 VLASAIATHAKIRD 254 022Der f 1 122 ATESAYLAYRNTSLD 255 025 Der p 1 159 RGIEYIQHNGVVQES 256 031Der p 2  83 QQYDIKYTWNVPKIA 257 117 Der p 4 383 EIYNMVKFRMIAGQE 258 122Der p 1 169 QESYYRYVAREQSSRR 259 HDM203B Der p 1 DLRQMRTVTPIRMQGGSGS 260HDM03W Der p 1 ELVDSASQHG 261 HDM101A Der p 1 NYSQIYPPNVNKIREA 262HDM201 Der p 1 ESVKYVQSNGGAI 263 HDM205 Der p 1 SYYRYVAREQS 264 HDM26BDer p 2 GVLASAIATHAKIR 265 HDM35A Der p 7 RGLKQMKRVGDANV

Table 6 shows additional peptides suggested for peptide combinations ofthe invention.

Example 2 Assembling a Donor Population

This example includes a description of how to compose a donor populationof house dust mite allergic individuals that represent a worldwidepopulation with respect to HLA Class II allele repertoire.

Donors (n=59) from the Copenhagen area were recruited by determiningimmunological reactivity to house dust mite allergen extract and byconfirming clinical history consistent with house dust mite allergy.Donors with detectable specific IgE levels towards Der p (extract) orDer f (extract) were included.

Each donor was genotyped with respect to their HLA loci DRB1, DRB3,DRB4, DRB5, DP, and DQ by the vendor Proimmune using PCR amplificationby the Tier 1 method. In short, the PCR-sequence specificoligonucleotides (PCR-SSOP) were used to resolve major allele groups to4 digits, with a certain degree of degeneracy between highly relatedalleles. PCR-SSOP: The genomic DNA was amplified using PCR and thenincubated with a panel of different oligo-nucleotide probes, which havedistinctive reactivity with different HLA-types. Table 7 shows the HLAclass II allele repertoire of the initial donor population and that thisdonor population represent 23 different HLA-DRB1 alleles.

For the purpose of calculating worldwide HLA coverage of the donorpopulation, there were selected a fraction (28 alleles) of theoriginally detected alleles of Table 7, because this fraction of alleleswere available for determining which HLA alleles the peptides are ableto bind to. Table 8 shows the worldwide HLA allele frequencies(calculated) of the limited set of 28 alleles (Table 8). The frequenciesrepresent an average frequency across several world-wide populations. Indetail: Average haplotype and phenotype frequencies for individualHLA-DRB1 alleles are based on MHC data available at The Allele FrequencyNet Database (AFND)<URL:http://www.allelefrequencies.net. As anestimated world wide allele distribution is used frequencies from thefour major ethnical groups, Hispanics, Caucasians, African Americans,and Asians. The frequencies are calculated as the simple mean of thefrequencies from population IDs, 1514, 1513, 2419, and 2420,respectively. Each ethnical group consists of data from more than 1000individuals. Average haplotype and phenotype frequencies for otheralleles are based on MHC data available at dbMHC (available at theinternet site <URL:http://www.ncbi.nlm.nih.gov/projects/gv/mhc/). dbMHCdata considers prevalence in Europe, North Africa, North-East Asia, theSouth Pacific (Australia and Oceania), Hispanic North, South America,American Indian, South-East Asia, South-West Asia, and Sub-SaharanAfrica populations. DP and DRB3/4/5 frequencies consider only the betachain frequency, given that the DRA chain is largely monomorphic, andthat differences in DPA are not hypothesized to significantly influencebinding. Frequency data are not available for DRB3/4/5 alleles. However,because of linkage with DRB1 alleles, coverage for these specificitiesmay be assumed as follows: DRB3 with DR3, DR11, DR12, DR13 and DR14;DRB4 with DR4, DR7 and DR9; DRB5 with DR15 and DR16. Specific allelefrequencies at each B3/B4/B5 locus are based on published associationswith various DRB1 alleles, and assume only limited variation at theindicated locus.

HLA allele frequencies shown in Table 8 were used to calculate thefraction of a worldwide population that would be covered by this subsetof alleles. As shown in FIG. 21 the selected allele subset from eachsingle locus individually represents between 15 and 97% of a worldwidepopulation, and the cumulated population coverage amounts to about 100%.

21 different HLA-DRB1 alleles were found in the donor population and areshown in Table 7. These alleles will be present in 89% of a worldwidepopulation according to the frequencies of Table 8. A final donorpopulation of 47 individuals was then assembled, and the HLA-DRB1alleles from this group are found in 85% instead of 89% of a worldwidepopulation. The final donor population (n=47) has 25 of the 28 allelesshown in Table 8 and a global population HLA coverage of about 100%could be estimated. Thus, the donor population may represent a globaldonor population with respect to the most frequent HLA Class II alleles.

TABLE 7 HLA alleles Table 7 - HLA Class II alleles found in the initialdonor population DRB DPA DQA DRB1_0101 DPA10103-DPB10101DQA10101-DQB10201 DRB1_0103 DPA10103-DPB10201 DQA10101-DQB10202DRB1_0301 DPA10103-DPB10301 DQA10101-DQB10301 DRB1_0401DPA10103-DPB10401 DQA10101-DQB10302 DRB1_0404 DPA10103-DPB10402DQA10101-DQB10501 DRB1_0405 DPA10103-DPB10501 DQA10101-DQB10503DRB1_0406 DPA10103-DPB10601 DQA10101-DQB10603 DRB1_0407DPA10103-DPB11001 DQA10102-DQB10201 DRB1_0701 DPA10103-DPB110401DQA10102-DQB10202 DRB1_0801 DPA10103-DPB110501 DQA10102-DQB10301DRB1_0803 DPA10103-DPB11101 DQA10102-DQB10302 DRB1_0901DPA10103-DPB111101 DQA10102-DQB10303 DRB1_1101 DPA10103-DPB11301DQA10102-DQB10402 DRB1_1103 DPA10103-DPB11501 DQA10102-DQB10502DRB1_1104 DPA10103-DPB11601 DQA10102-DQB10602 DRB1_1109DPA10103-DPB11701 DQA10102-DQB10603 DRB1_1201 DPA10103-DPB12301DQA10102-DQB10604 DRB1_1301 DPA10103-DPB15901 DQA10102-DQB10609DRB1_1302 DPA10201-DPB10101 DQA10103-DQB10201 DRB1_1303DPA10201-DPB10201 DQA10103-DQB10202 DRB1_1401 DPA10201-DPB10301DQA10103-DQB10301 DRB1_1501 DPA10201-DPB10401 DQA10103-DQB10302DRB1_1601 DPA10201-DPB10402 DQA10103-DQB10501 DRB3_0101DPA10201-DPB10501 DQA10103-DQB10601 DRB3_0201 DPA10201-DPB10901DQA10103-DQB10603 DRB3_0202 DPA10201-DPB11001 DQA10201-DQB10201DRB3_0301 DPA10201-DPB11101 DQA10201-DQB10202 DRB4_0101DPA10201-DPB11301 DQA10201-DQB10301 DRB4_0103 DPA10201-DPB11401DQA10201-DQB10302 DRB5_0101 DPA10201-DPB11701 DQA10201-DQB10303DRB5_0202 DPA10201-DPB12301 DQA10201-DQB10501 DPA10202-DPB10101DQA10201-DQB10602 DPA10202-DPB10201 DQA10201-DQB10603 DPA10202-DPB10401DQA10201-DQB10604 DPA10202-DPB10402 DQA10201-DQB10609 DPA10202-DPB10501DQA10301-DQB10201 DQA10301-DQB10202 DQA10301-DQB10301 DQA10301-DQB10302DQA10301-DQB10303 DQA10301-DQB10402 DQA10301-DQB10501 DQA10301-DQB10502DQA10301-DQB10503 DQA10301-DQB10601 DQA10301-DQB10602 DQA10301-DQB10603DQA10301-DQB10604 DQA10401-DQB10301 DQA10401-DQB10302 DQA10401-DQB10402DQA10401-DQB10602 DQA10501-DQB10201 DQA10501-DQB10202 DQA10501-DQB10301DQA10501-DQB10302 DQA10501-DQB10303 DQA10501-DQB10402 DQA10501-DQB10501DQA10501-DQB10602 DQA10501-DQB10603 DQA10505-DQB10202 DQA10505-DQB10301DQA10505-DQB10302 DQA10505-DQB10501 DQA10510-DQB10301 DQA10510-DQB10604

This table shows the HLA Class II allele repertoire of the initial donorpopulation.

TABLE 8 HLA alleles selected for prediction of HLA worldwide coverageTable 8 - HLA frequencies in a worldwide population Alleles (n = 13)Frequency Alleles (n = 15) Frequency DPA10201-DPB10101 0.084 DRB1_01010.043 DPA10103-DPB10201 0.092 DRB1_0301 0.077 DPA10103-DPB10301 0.07DRB1_0401 0.034 DPA10103-DPB10401 0.201 DRB1_0405 0.023DPA10103-DPB10402 0.236 DRB1_0701 0.102 DPA10202-DPB10501 0.115DRB1_0802 0.027 DPA10201-DPB11401 0.038 DRB1_0901 0.040DQA10501-DQB10201 0.058 DRB1_1101 0.057 DQA10501-DQB10301 0.195DRB1_1201 0.023 DQA10301-DQ810302 0.1 DRB1_1302 0.045 DQA10401-DQB104020.066 DRB1_1501 0.074 DQA10101-DQB10501 0.076 DRB3_0101 0.14DQA10102-DQB10602 0.076 DRB3_0202 0.189 DRB4_0101 0.237 DRB5_0101 0.083

Table 8 shows the HLA allele frequencies in a worldwide population for afraction (28 HLA alleles) of the alleles found in the initial donorpopulation. These allele frequencies were used in the prediction ofdonor HLA worldwide coverage shown in FIG. 18.

Example 3 Screening for T Cell Reactivity

This example includes a description of how peptides (singly or incombination) were screened for T cell reactivity in the donorpopulation.

The T cell reactivity to peptides disclosed herein was determined eitherby measuring T cell proliferation of T cell lines specific to theallergens investigated or by measuring the cytokine production ofallergen-specific T cells obtained from cultured PBMCs.

Establishing Cultured PBMCs and T-Cell Lines (TCL):

TCL specific to the six allergens rproDer p 1, rproDer f 1, rDer p 2,rDer f 2, Der p 4 and Der p 7, respectively or specific to thecombination of all six allergens were established from peripheral bloodmononuclear cells (PBMCs) of each donor.

PBMCs were isolated from freshly drawn heparinized blood by gradientcentrifugation on lymphoprep (Nycomed, Norway), washed twice andre-suspended in RPMI 1640 medium with HEPES and ultraglutamine (Cambrex,Belgium) supplemented with 5% v/v AB-serum (Cambrex, Belgium), 100units/ml penicillin, and 0.1 mg/ml streptomycin (Sigma, St Louis, USA)(referred to as AB-medium). Isolated PBMCs were CD8 depleted by Macsmagnetic depletion according to the manufacturer's instructions(Miltenyi Biotec, Bergisch Gladbach, Germany). CD8-depleted PBMC(2×106/ml) were stimulated in 1 ml bulk cultures in AB medium in 24 wellplates (Nunc, Denmark) with a mixture of recombinant allergens: rDer p1,rDer f1, r Derp2, rDerf2, rDerp4, rDerp7, 1 μg/ml of each, for 14 days.An amount of 65 U, 30 U, and 30 U recombinant IL-2 (Chiron, USA) wereadded per well at days 5, 6 and 7, respectively.

After 14 days, T-cells were isolated, washed and one aliquot was usedfor determination of the cytokine production, e.g. IL-5, by ELISpotassay (Enzyme-Linked ImmunoSpot) as described below. The remainingT-cells were re-stimulated in AB-medium with autologous PBMCs (106/well,irradiated 2500 Rad), allergens as above (1 μg/ml), and PHA-P (0.5μg/ml, Difco, Detroit, Mich., USA). rIL-2 was added at day 3, 4 and 5.10 days after re-stimulation T-cells are isolated, washed and used for Tcell proliferation assay as described below. Remaining cells are frozenfor later thawing and re-stimulation. The lines are kept in culture withre-stimulation every 10 days with allogeneic EBV B-cells (10⁵/well,irradiated 3500 Rad), allogeneic PBMCs (10⁶/well, irradiated 2500 Rad),and 0.5 μg/ml PHA-P and addition of rIL-2 at days 3-5. The cell linecultures are terminated after a period of 5 weeks, so all ELISpot dataare obtained after 14 days of culture whereas proliferative responsesare obtained after 24 or 34 days in culture

Alternatively, allergen-specific T cells were obtained in the followingmanner; PBMCs were thawed and cultured in RPMI 1640 (Ω Scientific,Tarzana, Calif.) supplemented with 5% human AB serum (Cellgro, Herndon,Va.) at a density of 2×10⁶ cells/ml in 24-well plates (BD Biosciences,San Jose, Calif.) and stimulated with a mixture of recombinantallergens: rDer p1, rDer f1, r Derp2, rDerf2, rDerp4, rDerp7, 1 μg/ml ofeach. Cells were kept at 37° C., 5% CO₂ and additional IL-2 (10 U/ml,eBioscience, San Diego, Calif.) was added every 3 days after initialantigenic stimulation. On day 14, cells were harvested and screened forreactivity against either selected peptides from Der p1, Der f1, Der p2,Der f2, Der p4 or Der p7 or peptide pools consisting on average of 20peptides. On day 17, peptides from positive pools were testedindividually to identify the reactive epitopes.

ELISpot assays. The production of IL-5 and IFN-γ from the cultured PBMCsdescribed above in response to stimulation with a peptide describedherein was measured by ELISpot as described in Oseroff C et al, 2010.Briefly, flat-bottom 96-well nitrocellulose plates (Millipore, Bedford,Mass.) were prepared according to the manufacturer's instructions andcoated with 10 μg/ml anti-human IL-5 and anti-human IFN-γ. The next day,plates were washed, blocked and cells (1×10⁵ cells/well) were plated andincubated with single peptide, peptide pool or a mixture of Der p andDer f (10 μg/ml, 5 μg/ml and 5 μg/ml, respectively). After 24 hours,cells were removed and plates were incubated with 2 μg/ml biotinylatedanti-human IL-5 Ab (clone 5A10; Mabtech) and anti-human IFN-γ-HRP (clone7-B6-1-HRP; Mabtech) at 37° C. After 2 hours, plates were washed andavidin-alkaline phosphatase-complex was added (Vector Laboratories,Burlingame, Calif.) for 1 h at RT. Alkaline phosphatase-conjugated spotswere developed with Vector Blue Substrate Kit (Vector Labs, Burlingame,Calif.). Horseradish Peroxidase-conjugated spots were developed with3-amino-9-ethylcarvazole solution (Sigma-Aldrich, St. Louis, Mo.).Criteria for peptide positivity were 20 SFCs/10⁶ PBMCs, p≦0.05stimulated cells compared to background, and a stimulation index (SI)≧2.

T Cell Proliferation Assay:

The capacity of the different peptides to stimulate allergen specific Tcells is analyzed in a standard 72 h T cell proliferation assay, asdescribed in Henmar H et al., Clin Exp Immunol 2008; 153β):316-23.

Cytokine Measurements:

Alternative to the ELISpot assay, the cytokine production of T cells canbe measured in cell culture supernatants harvested at day 1 of theprocedure for ELISpot assays or at day 2 of the procedure use forproliferation assays by analyzing the supernatants by MesoScale orMagPix analysis. The design of both assays resemble ELISA assays withthe capture antibodies of several different specificities spotted ineach well of a 96 well plate (Mesoscale, #144259) or the individualcatching antibodies attached to beads that can be mixed to the finalassay reagent (MagPix #230608) and both assays are developed to analyzevarious different cytokines or cellular mediators in a single sample.The cytokines IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, and IFN-g can bemeasured by Mesoscale, whereas IL-4, IL-5, IL-9, IL-10, IL-12, IL-13,IL-17, IL-22, IL-31 can be measured by MagPix.

In the present set-up, the cytokine production was evaluated withrespect to cytokine IL-5, which is predominantly produced by Th2 cells,but the evaluation could have been performed for other Th2-cytokines aswell, e.g. IL-4, IL-13 or others. Finally, the cytokine production couldhave been evaluated with IL-10, which may be an indication of generationof regulatory T cells. This can be performed with FluoroSpot techniqueas replacement of ELISpot.

In addition, future evaluation of cytokine production from Peptide Mixesmay be performed by Ex-Vivo FluoroSpot or EliSpot analysis of cytokinesinduced following peptide stimulation of PBMCs without any previousallergen stimulation.

Results:

FIGS. 1 to 4 show the percentage of donors that respond in the T-cellproliferation assay when T cells in vitro are exposed to the 20merspeptides of Tables 2 and 3. FIGS. 5 to 8 show the percentage of donorsthat responds in the T-cell proliferation assay when T cells in vitroare exposed to the 15mers peptides of Tables 4 and 5. Peptides to whicha higher fraction of the donor population respond to (e.g. more than20%, 25%, 30%, 40%, 50% of the donor population responds to) can beextracted from the figures and are listed in Tables 9 and 10 shownbelow. Those peptides are herein named “high responder peptides”. Wheretwo overlapping 15mers peptides both are considered high responderpeptides, the redundant amino acid sequence having a length of 20 aminoacids was assembled and is also shown in Tables 9 and 10 (SEQ ID NOS:272-285). The two tables also indicate peptides that were selected forinitial screening of peptide combinations in order to assemble peptidecombinations with high coverage. These are herein named “parentpeptides” (parent peptides are indicated with their Pep ID or SEQ ID inbold in Tables 9 and 10). Among peptides screened from Der p 1 and Der f1, the following peptides were considered “parent peptides”: peptideshaving an amino acid sequence of SEQ ID NOs: 9 (pep-041), 10 (pep-042),11 (pep-043), 12 (pep-044), 42 (pep-072), 254 (pep-022), 15 (pep-047),266 (pep-123), 255 (pep-025), 17 (pep-049), 46 (pep-075), 18 (pep-050),258 (pep-122), 267 (pep-124), 20 (pep-052), 49 (pep-078), 21 (pep-053),268 (pep-130), 22 (pep-054), 23 (pep-055), 52 (pep-081), 26 (pep-058),29 (pep-061), 58 (pep-087), 251 (pep-010), 252 (pep-011) and 272.

Among peptides screened from Der p 2 and Der f 2, the following peptideswere considered “parent peptides”: Peptides with SEQ ID NOs: 71(pep-100), 72 (pep-101), 60 (pep-089), 61 (pep-090), 73 (pep-102), 249(pep-002), 62 (pep-091), 63 (pep-092), 77 (pep-106), 67 (pep-096), 271(pep-131), 79 (pep-108), 256 (pep-031), 270 (pep-126), 81 (pep-109), 269(pep-125), 70 (pep-099) and 82 (pep-110).

TABLE 9 Peptides from Der p 1 and Der f 1 with “high”responder frequency in T cell assays SEQ Peptide sequence  ID Pep aaPeptide from Der p 1 or  NO: ID: Species: length: group:Der f 1 or both (pf1)  1  36 (position number)  90 p1 15 VKYVQSNGGAINHLS 2  76 280 p1 20 DLNAETNACSINGNAPAEI  98 p1 15 DLNAETNACSINGNA   9 041p1 20  3 TNASSINGNAPAEIDLRQM  99 p1 15 TNACSINGNAPAEI  10 042 p1 20  4APAEIDLRQMRTVTPIRMQG 259 203B p1 19 DLRQMRTVTPIRMQGGSG 102 p1 15DLRQMRTVTPIRMQG 161 f1 15 DLRSLRTVTPIRMQG 281 p1 20 DLRQMRTVTPIRMQGGCGSC282 f1 20 DLRSLRTVTPIRMQGGCGSC  11 043 pf1 20  5 RTVTPIRMQGGSGSSWAFSG103 pf1 15 RTVTPIRMQGGCGSC 281 p1 20 DLRQMRTVTPIRMQGGCGSC 282 f1 20DLRSLRTVTPIRMQGGCGSC  6 110  12 044 pf1 20 GSGSSWAFSGVAATESAYLA 105 pf115 GCGSCWAFSGVAATE 283 pf1 20 GCGSCWAFSGVAATESAYLA 106 pf1 15WAFSGVAATESAYLA  42 072 f1 20  7 VAATESAYLAYRNTSLDLSE 166 f1 15VAATESAYLAYRNTS 254 022 f1 15 AATESAYLAYRNTSLD  8 140  15 047 pf1 20QELVDSASQHGSHGDTIPRG 111 pf1 15 QELVDCASQHGCHGD 270 pf1 20QELVDCASQHGCHGDTIPRG 112 pf1 15 CASQHGCHGDTIPRG  9 158 266 123 p1 22RGIEYIQHNGVVQESYYRYVAR 255 025 p1 15 RGIEYIQHNGVVQES  17 049 p1 20IEYIQHNGVVQESYYRYVAR  46 075 f1 20 IEYIQQNGVVEERSYPYVAR 271 f1 20TIPRGIEYIQQNGVVEERSY 114 p1 15 TIPRGIEYIQHNGVV 173 f1 15 TIPRGIEYIQQNGVV115 p1 15 IEYIQHNGVVQESYY 174 f1 15 IEYIQQNGVVEERSY  18 050 p1 20 10QESYYRYVAREQSSRRPNAQ 258 122 p1 16 QESYYRYVAREQSSRR 267 124 p1 21VQESYYRYVAREQSSRRPNAQ 117 p1 15 QESYYRYVAREQSCR 176 f1 15EERSYPYVAREQQCR 11 185 120 p1 15 RPNAQRFGISNYCQI  20 052 p1 20 12RFGISNYSQIYPPNANKIRE  49 078 f1 20 HYGISNYSQIYPPDVKQIRE 121 p1 15RFGISNYCQIYPPNA 180 f1 15 HYGISNYCQIYPPDV  21 053 p1 20 13YPPNANKIREALAQTHSAIA 208 268 130 p1 22 14 REALAQTHSAIAVIIGIKDLDA  22 054p1 20 ALAQTHSAIAVIIGIKDLDA  23 055 p1 20 15 VIIGIKDLDAFRHYDGRTII  52 081f1 20 VIIGIKDLRAFQHYDGRTII 272 p1 20 KDLDAFRHYDGRTIIQRDNG 273 f1 20KDLRAFQHYDGRTIIQHDNG 128 p1 15 KDLDAFRHYDGRTII 187 f1 15 KDLRAFQHYDGRTII129 p1 15 FRHYDGRTIIQRDNG 188 f1 15 FQHYDGRTIIQHDNG 16 250  26 058 p1 20HAVNIVGYSNAQGVDYWIVR 133 p1 15 HAVNIVGYSNAQGVD 192 f1 15 HAVNIVGYGSTQGVD274 p1 20 YQPNYHAVNIVGYGSTQGVD 191 f1 15 YQPNYHAVNIVGYGS 17 280  29 061p1 22 GYGYFAANIDLMMIEEYPYVVI  58 087 f1 23 GYGYFQAGNNLMMIEQYPYVVIM 251010 18 DNGYGYFAANIDLMMIEE 252 011 p1 14 NGYGYFAANIDLMM 140 p1 15AANIDLMMIEEYPYV 199 f1 15 QAGNNLMMIEQYPYV

TABLE 10 Peptides from Der p 2 and f 2 showinghigh responder frequency in T cell assays. SEQ Peptide sequence ID Pepaa Peptide from Der p 2 or  NO: ID: Species: length: group:Der f 2 both (pf2)   1  71 100 f2 18 DQVDVKDSANNEIKKVMVD  72 101 f2 2019 NNEIKKVMVDGSHGSDPSII 227 f2 15 NEIKKVMVDGCHGSD  60 089 p2NHEIKKVLVPGSHGSEPSII 275 f2 20 KDCANNEIKKVMVDGCHGSD 226 f2KDCANNEIKKVMVDG  61 090 p2 20 20 GSHGSEPSIIHRGKPFQLEA  73 102 f2 20GSHGSDPSIIHRGKPFTLEA 276 p2 20 CHGSEPCIIHRGKPFQLEAV 277 f2 20CHGSDPCIIHRGKPFTLEAL 205 p2 15 CHGSEPCIIHRGKPF 229 f2 15 CHGSDPCIIHRGKPF249 002 p2 13 SIIHRGKPFQLEA* 206 p2 15 PCIIHRGKPFQLEAV 230 f2 15PCIIHRGKPFTLEAL 21  30  62 091 p2 20 HRGKPFQLEAVFEANQNTKT 208 p2 15QLEAVFEANQNTKTA  63 092 p2 20 22 VFEANQNTKTAKIEIKASID 278 f2 20FDANQNTKTAKIEIKASLDG 233 f2 15 FDANQNTKTAKIEIK 210 p2 15 NTKTAKIEIKASIDG234 f2 15 NTKTAKIEIKASLDG 23  60  77 106 f2 20 GLEIDVPGIDTNASHFMKSP 238f2 15 PGIDTNACHFMKCPL 24  80  67 096 p2 20 LVKGQQYDIKYTWNVPKIAP 271 131p2 21 LVKGQQYDIKYTWNVPKIAPK  79 108 f2 20 LVKGQQYDAKYTWNVPKIAP 256 031p2 15 QQYDIKYTWNVPKIA 270 126 p2 15 KGQQYDIKYTWNVPKIA 279 f2 20YDAKYTWNVPKIAPKSENVV 242 f2 15 YDAKYTWNVPKIAPK 243 f2 15 TWNVPKIAPKSENVV100  81 109 f2 25 KSENVVVTVKLVGDNGVLAS 221 p2 15 SENVVVTVKVMGDDG 245 f215 SENVVVTVKLVGDNG 246 f2 15 VTVKLVGDNGVLACA 269 125 p2 20 26VMGDNGVLASAIATHAKIRD  70 099 p2 20 VMGDDGVLASAIATHAKIRD  82 110 f2 20LVGDNGVLASAIATHAKIRD 223 p2 15 MGDDGVLACAIATHA 247 f2 15 VGDNGVLACAIATHA264 26B p2 14 GVLASAIATHAKIR* 224 p2 15 GVLACAIATHAKIRD 248 f2 15GVLACAIATHAKIRD 253 012 p2 14 VLASAIATHAKIRD*

Example 4 Modification of Parent Peptides

This example describes modifications of parent peptides to improve theaqueous solubility, in particular to increase the solubility in anaqueous solution having pH in a physiologically acceptable range, e.g.from 6 to 8. Solubility is closely related to the ratio betweenhydrophilic and hydrophobic amino acid residues and the net charge stateof the peptide. Peptides have zero net charge at pH=pI, and would beexpected to show the lowest solubility at this pH. Table 11bdemonstrates that the pI (theoretically estimated) increases along withthe net charge by adding one or more arginine residues to the parentpeptides pep-058, pep-075 and pep-130 and that it is possible toincrease the pI to above 8. Table 11b also shows that the solubility atpH 7 (evaluated by visual inspection) is increased for some of themodified peptides by adding one or more arginine residues to the N-and/or C-terminus. The solubility of these peptides was increased at pHvalues outside the physiological range (data not shown).

Table 11a shows other examples on how to modify the pI and the netcharge by adding one or more amino acid residues from the wild typeallergen to the N- and/or C-terminus of the peptides pep-049, pep-054,pep-031, pep-096, pep-075 and pep-130. The pI and net charge wereestimated using known tools in the art. Table 11a also showsmodifications made with the purpose of avoiding an N-terminal “Q” aminoacid residue in pep-050 and to avoid the two adjacent amino acids “DG”in the sequence of pep-099.

The net charge of a peptide may be changed by acetylation of theN-terminal amino acid residue, which removes one positive charge (=netcharge decreased by 1) or by the amidation of the C-terminal amino acidresidue, which removes one negative charge (=net charge increased by 1).Table 11c shows examples on C-terminus amidation of peptides pep-058,pep-075 (along with addition of the RG amino acid residues at theN-terminus), pep-110, pep-130, pep-091 and pep-123, which demonstratethat the pI and net charge increase.

Peptides were tested for their ability to dissolve in aqueous solutionsat different pH values. In short, each of the peptides were dissolved inwater (pH about 5-6), hydrochloride solution at pH 2 (10 mM HCl),acetate buffer with pH 5 (20 mM acetate and 140 mM sodium chloride),phosphate buffer with pH 7 (20 mM phosphate and 140 mM sodium chloride)or bistrispropate buffer with pH 9 (20 mM bitrispropane and 140 mMsodium chloride, respectively, to produce a final molar concentration ofthe peptide of about 0.25 mM or 1 mM. Optionally, about 20% DMSO may bepart of the solution. For comparison reasons, peptides were alsodissolved in acetonitrile or DMSO. The solutions were inspected visuallybefore and after centrifugation for turbidity, presence ofparticles/aggregates. In addition, presence ofturbidity/particles/aggregates were detected by optical density (OD),but might also be detected by size-exclusion chromatography. Sub-visualparticles may also be detected by dynamic light scattering (DLS)analysis. The solubility and stability of each peptide were alsoinvestigated using HPLC, e.g. RP-HPLC. For example, each of thesolutions were injected onto the HPLC and the peak height or peak areaof each of the peptides were compared to the corresponding peptide of achromatogram of peptides dissolved in acetonitrile or DMSO—as peptideswere assumed to be fully dissolved and stable in these solvents.

Table 11a to 11c—Examples of Peptides with Changes in Solubility

TABLE 11a Addition of amino acid residue(s) from wild type isoform SEQPep Modified Change in ID ID from Change charge at Solubility NO NoSequence Peptide: in pI pH 7 at pH 7 266 123 RGIEYIQHNGVVQESYYRYVAR 0497.6 to 9.3   0.1 to 1.1 Slight turbid 267 124 VQESYYRYVAREQSSRRPNAQ 050268 130 REALAQTHSAIAVIIGIKDLDA 054 5.1 to 5.3  Unchanged Slight (-0.9)turbid 269 125 VMGDNGVLASAIATHAKIRD 099 270 126 KGQQYDIKYTWNVPKIA 0319.5 to 9.9     1 to 2   Clear 271 131 LVKGQQYDIKYTWNVPKIAPK 0969.9 to 10.1    2 to 3   Clear 272 134 RGIEYIQQNGVVEERSYPYVAR 0754.6 to 7.0    -1 to 0   Clear 273 135 KIREALAQTHSAIAVIIGIKDLDA 1305.3 to 7.8  -0.9 to 0.1 Slight turbid

TABLE 11b Addition of Arginine(s) Net Solubility SEQ charge at pH IDPeptide at 7 (visual NO ID Sequence pI pH 7 inspection){circumflex over( )} 058 HAVNIVGYSNAQGVDYWIVR 7.7 0.1 Slight turbid 276 136RHAVNIVGYSNAQGVDYWIVR 9.6 1.1 Slight turbid 277 137RHAVNIVGYSNAQGVDYWIVRR 10.2 2.1 Clear 278 138 RRHAVNIVGYSNAQGVDYWIVRR11.1 3.1 Slight turbid 274 132 RRRRHAVNIVGYSNAQGVDYWIVR 11.8 4.1Slight turbid 275 133 RRHAVNIVGYSNAQGVDYWIVRRR 11.8 4.1 Clear 075IEYIQQNGVVEERSYPYVAR 4.6 -1 Turbid 279 139 RIEYIQQNGVVEERSYPYVAR 7 0Clear 280 140 RIEYIQQNGVVEERSYPYVARR 9.4 1 Clear 281 141RRIEYIQQNGVVEERSYPYVARR 9.9 2 Clear 282 142 RRIEYIQQNGVVEERSYPYVARRR10.4 3 Clear 268 130 REALAQTHSAIAVIIGIKDLDA 5.3 -0.9 Slight turbid 283143 RREALAQTHSAIAVIIGIKDLDA 7.8 0.1 Slight turbid 284 144RREALAQTHSAIAVIIGIKDLDAR 10.1 1.1 Clear 285 145RRREALAQTHSAIAVIIGIKDLDAR 11.2 2.1 Clear 286 146RRREALAQTHSAIAVIIGIKDLDARR 11.8 3.1 Clear

TABLE 11c Amidation (-NH2) Change in Pep From Change charge atSolubility ID No Sequence Peptide: in pI* pH 7* at pH 7 147HAVNIVGYSNAQGV 058 7.7 to 9.6   0.1 to 1.1 ND DYWIVR-NH2 148RGIEYIQQNGVVEE 075 4.6 to 9.4    -1 to 1   Slight RSYPYVAR-NH2 turbid149 LVGDNGVLASAIAT 110 7.8 to 10.1  0.1 to 1.1 Clear HAKIRD-NH2 150KIREALAQTHSAIA 130 5.3 to 9.9  -0.9 to 1.1 Clear VIIGIKDLDA-NH2 151HRGKPFQLEAVFEA 091 9.9 to 10.6  1.1 to 2.1 Clear NQNTKT-NH2 152RGIEYIQHNGVVQE 123 9.3 to 9.8   1.1 to 2.1 ND SYYRYVAR-NH2

Example 5 Selecting Candidates for Peptide Combinations

This example includes a description of how to assemble peptidecombinations (pep-mixes), which with high likelihood would cover theworldwide (WW) HLA Class II allele repertoire and which will exploresatisfactorily high frequency of T cell recognition in a worldwidepopulation. Such peptide combinations would be eligible for peptidevaccines offered to a subject of any geographic region in the world withthe expectation that the immune system will recognize at least one ofthe peptides in the peptide combination.

A peptide may be eligible for peptide combinations of the invention ifit meets a first criterion of having high WW HLA coverage, preferably ofabove 0.4 (40% of WW population). The potential WW population coverageafforded by a peptide was determined on the basis of predicted capacityto bind a panel of 83 different HLA DR, DQ and DP molecules (Table 17).The coverage was calculated essentially as previously described in theliterature (Bui et al. 2006; Sidney et al. 1996; Sidney et al. 2010a;Sidney et al. 2010b) based on MHC data available at dbMHC (available atthe internet site <URL:http://www.ncbi.nlm.nih.gov/projects/gv/mhc/).)(Meyer et al. 2007) and http://www.allelefrequencies.net/ (Middleton etal. 2003). These databases consider prevalence in Australia, Europe,North Africa, North America, North-East Asia, Oceania, Other, SouthAmerica, South-East Asia, South-West Asia, and Sub-Saharan Africa. Thesepopulations are additionally inclusive of several sub-populations. Thepredictions and coverage calculations were performed with respect to the30 most prevalent alleles/haplotypes within the HLA loci, HLA-DRB1,HLA-DQ, and HLA-DP. For HLA-DQ and HLA-DP based MHC molecules both thealpha and the beta chains are in principle polymorphic, and the peptidespecificity of the complete molecule thus determined by both alleles. Asaccurate haplotype data are not available concerning the couplingbetween the genetically linked alpha and beta chains for HLA-DQ andHLA-DP loci, respectively, it was assumed that they are geneticallyunlinked in the frequency calculation of the final haplotypes. The 83considered alleles and the corresponding frequency data are displayed inTable 17. HLA-peptide binding predictions were conducted using the toolNetMHCIIpan-3.0 (Karosiene, Edita, Michael Rasmussen, Thomas Blicher,Ole Lund, Soren Buus, and Morten Nielsen. “NetMHCIIpan-3.0, a CommonPan-specific MHC Class II Prediction Method Including All Three HumanMHC Class II Isotypes, HLA-DR, HLA-DP and HLA-DQ.” Immunogenetics)available at the internet site <URL:http://www.cbs.dtu.dk/services/NetMHCIIpan-3.0>. The peptides wereconsidered positive to a given allele if the affinity was predicted tobe lower than 300 nM and have a fractile score lower than 30% asreported by the prediction tool. For each peptide the frequency of eachpredicted positive allele was summed for each of the loci and the finalpredicted population coverage was calculated.

According to a second criterion, a peptide eligible for a peptidecombination of the invention may have high frequency of T cellrecognition in the donor population, which may be found among the parentpeptides shown in Tables 9 and 10 or a variant thereof.

Table 12 lists examples of parent peptides initially selected forassembling peptide combinations in accordance with the first and secondcriterion described above together with their predicted worldwide HLAClass II coverage. Each peptide is also rated as A, B, C or D. Therating A denotes that the peptide has predicted WW HLA coverage above0.4 (40% of WW population) and is recognized by T cells with a highfrequency in the donor population. The rating B means that despitepredicted low HLA WW coverage, the peptide gave a high frequency in Tcell responses in the donor population investigated. The rating C meansa peptide having high HLA prediction, but seems to give a low frequencyin T cell recognition. The rating D means that the peptide had aborderline satisfactorily WW HLA coverage and T cell recognitionfrequency.

Table 13 shows the predicted WW HLA coverage of each of seven peptidesof a peptide combination suggested for treating house dust mite allergy(International patent application WO2009 022156).

TABLE 12 Example Candidate Peptides SEQ Predicted ID Parent PeptideWW HLA No peptide group Sequence coverage Rating 9 041 3TNASSINGNAPAEIDLRQM 0.8309 C 10 042 4 APAEIDLRQMRTVTPIRMQG 0.8684 A 11043 5 RTVTPIRMQGGSGSSWAFSG 0.6903 A 12 044 6 GSGSSWAFSGVAATESAYLA 0.9639A 42 072 7 VAATESAYLAYRNTSLDLSE 249 022 7 ATESAYLAYRNTSLD 0.6262 C 15047 8 QELVDSASQHGSHGDTIPRG 0      D 255 025 9 RGIEYIQHNGVVQES ND B 17049 9 IEYIQHNGVVQESYYRYVAR 0.9434 A 46 075 9 IEYIQQNGVVEERSYPYVAR 0.0924B 266 123 9 RGIEYIQHNGVVQESYYRYVAR A 258 122 10 QESYYRYVAREQSSRR 0.5776A 18 050 10 QESYYRYVAREQSSRRPNAQ 0.5776 A 20 052 12 RFGISNYSQIYPPNANKIRE0.3248 B 49 078 12 HYGISNYSQIYPPDVKQIRE 0.1907 B 21 053 13YPPNANKIREALAQTHSAIA 0.785  A 22 054 14 ALAQTHSAIAVIIGIKDLDA 0.9148 A268 130 14 REALAQTHSAIAVIIGIKDLDA A 23 055 15 VIIGIKDLDAFRHYDGRTII0.287  B 52 081 15 VIIGIKDLRAFQHYDGRTII 0.8372 A 26 058 16HAVNIVGYSNAQGVDYWIVR 0.7899 A 251 010 17 DNGYGYFAANIDLMMIEE 1      A 252011 17 NGYGYFAANIDLMM 0.9996 A 58 087 17 GYGYFQAGNNLMMIEQYPYVVIM 0.9996A 29 061 17 GYGYFAANIDLMMIEEYPYVVIL 1      A 71 100 18DQVDVKDSANNEIKKVMVD 72 101 19 NNEIKKVMVDGSHGSDPSII B 60 089 19NHEIKKVLVPGSHGSEPSII 0.2855 D 61 090 20 GSHGSEPSIIHRGKPFQLEA 0.8368 A 73102 20 GSHGSDPSIIHRGKPFTLEA 0.7825 A 249 002 20 SIIHRGKPFQLEA 0.8497 A62 091 21 HRGKPFQLEAVFEANQNTKT 0.9851 A 63 092 22 VFEANQNTKTAKIEIKASID77 106 23 GLEIDVPGIDTNASHFMKSP B 67 096 24 LVKGQQYDIKYTWNVPKIAP 0.8233 A271 131 24 LVKGQQYDIKYTWNVPKIAPK A 79 108 24 LVKGQQYDAKYTWNVPKIAP B 256031 24 QQYDIKYTWNVPKIA 0.8233 A 270 126 24 KGQQYDIKYTWNVPKIA A 81 109 25KSENVVVTVKLVGDNGVLAS 0.4565 A 70 099 26 VMGDDGVLASAIATHAKIRD 0.9688 A269 125 26 VMGDNGVLASAIATHAKIRD A 82 110 26 LVGDNGVLASAIATHAKIRD 0.9864A 253 012 26 VLASAIATHAKIRD 0.9154 A 257 117 p4 EIYNMVKFRMIAGQE 0.9921 C

TABLE 13 List of peptides of known peptide combination Belong toPredicted Peptide WW HLA ID No Species Sequence group No: coverageRating HDM03W p1 ELVDSASQHG   (8)* 0 HDM101A p1 NYSQIYPPNVNKIREA 120.1604 HDM201 p1 ESVKYVQSNGGAI None 0.3357 HDM203B p1DLRQMRTVTPIRMQGGSGS  4 0.8626 A HDM205 p1 SYYRYVAREQS 10 0.3441 HDM26Bp2 GVLASAIATHAKIR 26 0.9588 A HDM35A p7 RGLKQMKRVGDANV None 0 *PeptideHDM03W has less than 15 amino acid residues in overlap with a parentpeptide of peptide group 8, and thus not a variant peptide of a parentpeptide of peptide group 8.

Example 6 Assembling Peptide Combinations

Several peptide combinations (Table 14) with predicted high WW HLA ClassII coverage were assembled from the peptides selected in Table 12.Similar peptide combinations can be assembled using another peptide(substitute peptide) from the same peptide group, i.e. another peptidefrom the same peptide group shown in Tables 9 and 10.

TABLE 14 Peptide Combinations SEQ Parent group Peptide Combination No:ID NO: peptide Species No: 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 19 2021 22 23 249 002 p2 20 x x x 250 009 p1 None x 251 010 p1 17 x x x x x xx x 252 011 p1 17 X X x 253 012 p2 26 X x X x x x 254 022 f1 7 x X x x xx x 255 025 p1 9 x x 256 031 p2 24 X X x x 9 041 p1 3 x x 10 042 p1 4 11043 pf1 5 x X x x 12 044 pf1 6 x X x x x x 17 049 p1 9 X x 18 050 p1 10x x x 20 052 p1 12 22 054 p1 14 26 058 p1 16 x x 46 075 f1 9 x x x 49078 f1 12 52 081 f1 15 60 089 p2 19 x 62 091 p2 21 70 099 p2 26 x X x xx x x x x 71 100 f2 18 x 73 102 f2 20 x 81 109 f2 25 x x 82 110 f2 26 xX x x x x x x x 257 117 p4 X x x x 258 122 p1 10 X x X x x x 266 123 p19 268 130 p2 14 271 131 p2 24 No of Peptides: 5 5 5 7 5 7 5 5 5 5 3 5 43 5 5 4 5 5 5 SEQ Parent Group Peptide Combination No: ID NO: peptideSpecies No: 24 25 17 17a 17b 17c 17d 17f 17p 17l 17q 17s 17t 17u 17v17x* 249 002 p2 20 250 009 p1 None 251 010 p1 17 252 011 p1 17 253 012p2 26 254 022 f1 7 255 025 p1 9 256 031 p2 24 9 041 p1 3 X x x 10 042 p14 11 043 pf1 5 12 044 pf1 6 X x 17 049 p1 9 x 18 050 p1 10 X 20 052 p112 x 22 054 p1 14 x x 26 058 p1 16 X x x x x X x X X X x 46 075 f1 9 X xx X x X x X 49 078 f1 12 X 52 081 f1 15 x x 60 089 p2 19 62 091 p2 21 xx x x X X x x 70 099 p2 26 71 100 f2 18 X 73 102 f2 20 X 81 109 f2 25 Xx x 82 110 f2 26 x X x x x x X x x X X x x x 257 117 p4 258 122 p1 10266 123 p1 9 x X X X X 268 130 p2 14 X x X X x X x 271 131 p2 24 X x X xX x x X No of Peptides: 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 *Peptidecombination number 17x also contain pep-053 (shown in Table 12)

Table 14 shows examples of peptide combinations (“X” indicates that thepeptide is present in the peptide combination) with predicted broad WWHLA class II coverage. Peptide combination number 8 contains the sevenpeptides of Table 13.

Example 7 T Cell Responses of Peptide Combinations

Peptide combinations number 3, 4, 5, 8, 9, 10, 13, 16-25 of Table 14were initially tested for in vitro T cell responses as described abovefor single peptides. As shown in FIG. 9a the majority of the peptidecombinations produce T cell responses in a high fraction of the donorpopulation, such as more than about 60% to 70% of the donor population.Two peptide combinations, combination number 17 (5-peptide mix) andcombination number 23 (5-peptide mix) produce T cell responses in ahigher fraction of the donor population (such as above 80% of the donorpopulation) than other peptide combinations. Also of note is that two ofthe peptide combinations only contain 3 peptides (peptide combinationnumber 13 and 16), but still produce a T cell response in a highfraction of the population (more than 70% of the donor population). Suchpeptide combinations could be improved to produce a T cell response inan even higher fraction of the donor population, for example by adding apeptide listed in Table 12.

Additional peptide combinations were tested in T cell response assaystogether with peptide combination number 17 using a subset of 22 donorshaving about 88% worldwide HLA Class II coverage. FIG. 9b shows thatpeptide combination number 17f produces a T cell response in about 100%of the donor population tested in comparison to the 85% donor responseto peptide combination number 17 (FIG. 9c ). T cell responses for singlepeptides of combination 17f are also shown in FIG. 9b and indicates thatpeptide numbers 110 (a peptide group 26 peptide), 131 (a peptide group24 peptide) and 054 (a peptide group 14 peptide) resulted in a higherpercentage donor response than the other peptides of peptide combination17f (FIG. 9c ). The individual data of each peptide can be used tocalculate the percentage of donors responding to the peptidecombinations 17 and 17f in that there is a positive donor response ifthere is a response to at least one peptide in the combination. As shownhere, the calculated fraction of donors responding to peptidecombinations 17 and 17f based on individual peptide data correlates withthe fraction of donors responding to the same peptide combinationstested in T cell assays. Thus, the percentage of responders recognizinga peptide combination can be calculated using information about theindividual peptides that produce an in vitro T cell response in each ofthe donors tested.

This allows for calculating the percentage responders to other peptidecombinations comprising peptides of peptide combination 17f and 17. FIG.9d shows the percentage donor response as calculated for peptidecombinations 17l, 17p, 17q, 17s, 17t, 17u and 17v (compositions shown inTable 14) and shows that these will produce a T cell response in about80% to 90% of the donor population.

Further peptide combinations were evaluated using a subset of peptides(pep-058, pep-075, pep-091, pep-110, pep-123, pep-130 and pep-131) and asubset of 31 donors having a worldwide HLA Class II coverage of about88%. FIG. 9f shows the percentage of responding donors shown to respondto peptide combinations 17p, 17s, 17f, and 8 and a peptide combinationconsisting of only peptides pep-110, pep-130 and pep-131, when analyzedin a T cell assay. FIG. 9g shows the calculated percentage of respondersbased on the individual peptide data to peptide combinations 17p, 17s,17f, 3-pep-mix of 110+130+131 and 2-pep-mix of 110 and 131, which dataindicate that all the peptide combinations suggested in FIG. 9g willproduce a T cell response in about the same fraction of the donorpopulation, such as between 80 to 90% of the donor population.

The number of peptides that a donor of the donor population in averageresponds to may also be calculated using the information about how manyof the peptides in the peptide combination a donor is able to respondto. FIG. 9h shows the average number of peptides in peptide combinations17p, 17s, 17f, 3-pep-mix 110+130-131 and the 2-pep-mix 110+131 that adonor of the test population is able to respond to. The data indicatesthat the average number of peptides in mixes 17p, 17s and 17f is between2.5 to 3, while the average number of peptides decreases with fewerpeptides in the combination.

In still another experiment, the individual peptides 058, 075, 110, 123,130, 131 and the peptides of peptide combination 8 (HDM03W, HDM101A,HDM203B, HDM205, HDM26B and HDM35A) were tested in a T cell assay usinga subset of the original donor population.

FIG. 9i shows the percentage of donors responding to each of thepeptides tested. In the same T cell assay the peptide combination 17fand 8 were analyzed again (shown in FIG. 9j ). FIG. 9k shows thecalculated percentage donors responding to the further peptidecombinations were evaluated using a subset of peptides (pep-058,pep-075, pep-091, pep-110, pep-123, pep-130 and pep-131) and a subset of22 donors having about 78% worldwide HLA Class II coverage. FIG. 9lshows the percentage of responding donors shown to respond to peptidecombinations 17p, 17s, 17f, and 8 and a peptide combination consistingof only peptides pep-110, pep-130 and pep-131, when analyzed in a T cellassay using a subset of 31 donors having about 88% worldwide HLA ClassII coverage.

Example 8 First Choice Peptides

This example lists “first choice” peptides that may be used forassembling peptide combinations producing a T cell response in a highfraction of donors. These peptides have been shown to possess medium tohigh HLA Class II coverage and/or medium to high percentage respondersin T cell assays, but also appear to possess suitable pharmaceuticalproperties, such as satisfactorily solubility in aqueous solution in thepH range of 4 to 9 and to be manufacturable.

TABLE 15 List of first choice peptides SEQ Sequence ID Peptide Peptideshown in NO No group pI Table(s): 17 049 9 9, 12 266 123 9 9.3 9, 12 46 075* 9 4.6 9, 12 279 139 9 7.0 11b 280 140 9 9.4 11b 281 141 9 9.9 11b282 142 9 10.4 11b 272 134 9 11b 148 9 9.4 11c 152 9 9.8 11c 18 050 109, 12 267 124 10 9.9 11a 21 053 13 9.7 9, 12 22 054 14 9, 12 268  130*14 5.3 9, 12 283 143 14 7.8 11b 284 144 14 10.1 11b 285 145 14 11.2 11b286 146 14 11.8 11b 150 14 9.9 11c 273 135 14 11a 26  058* 16 7.7 9, 12276 136 16 9.6 11b 277 137 16 10.2 11b 278 138 16 11.1 11b 274 132 1611b 275 133 16 11.8 11b 147 16 9.6 11a 61 090 20 8.0 10, 12 73 102 208.0 10, 12 62 091 21 9.9 10, 12 151 21 10.6 11c 256 031 24 10, 12 67 09624 10, 12 270 126 24 9.9 11a 271 131 24 10, 12, 11a 81 109 25 7.0 10, 12253 012 26 10, 12 70 099 26 10, 12 82 110 26 10, 12 269 125 26 7.8 11a149 26 10.1 11c *peptides marked with an asterisk may cause somesolubility problems in which case a variant of the peptide may be usedinstead, e.g. a modification comprising one or more lysine or arginineresidues at the N- and/or C-terminal end or amidation.

Example 9 In Vitro HLA Class II Binding Analysis of Peptides

This example describes how to determine the HLA class II binding ofpeptides of the invention. The assay employed is a competitive MHC classII binding assay, wherein each peptide is analyzed for its ability todisplace a known control binder from each of the human MHC class IIallotypes shown in Table 8. Due to the nature of the competitive assay,the data for each peptide is determined as a ratio of its own IC50 tothat of the control peptide. Thus, a peptide that has an IC50 value thatis parity to the control peptide has an identical binding affinity,while peptides with a ratio less than one have a higher affinity andthose with a ratio greater than one have a lower affinity. The ratio ofIC50 may be determined at different cutoff concentrations, for exampleat 300 or 1000 nM.

Assays to quantitatively measure peptide binding to purified class IIMHC molecules are based on the inhibition of binding of a high affinityradiolabeled peptide to purified MHC molecules, and were performedessentially as detailed elsewhere (Sidney et al. 2008; Sidney et al.2010b, a; Greenbaum et al. 2011; Sidney et al. 2001, Sidney et al 2013,McKinney et al 2013). Briefly, 0.1-1 nM of radiolabeled peptide wasco-incubated at room temperature or 37° C. with purified MHC in thepresence of a cocktail of protease inhibitors. Following a two- tofour-day incubation, MHC bound radioactivity was determined by capturingMHC/peptide complexes on monoclonal Ab coated Lumitrac 600 plates(Greiner Bio-one, Frickenhausen, Germany), and measuring bound cpm usingthe TopCount (Packard Instrument Co., Meriden, Conn.) microscintillationcounter. In the case of competitive assays, the concentration of peptideyielding 50% inhibition of the binding of the radiolabeled peptide wascalculated. Under the conditions utilized, where [label]<[MHC] andIC50≧[MHC], the measured IC50 values are reasonable approximations ofthe true Kd values (Cheng and Prusoff 1973; Gulukota et al. 1997). Eachpeptide was tested at six different concentrations covering a100,000-fold dose range in three or more independent experiments. As apositive control, the unlabeled version of the radiolabeled probe wasalso tested in each experiment.

Table 16a shows the HLA Class II alleles for which the HLA bindingaffinity of a selection of peptides has been measured. A positivebinding is indicated in the Table with an “x”, which refers to a bindingaffinity IC50<1000 nM.

Table 16b shows the minimal number of alleles bound by each of thepeptides and the Class II HLA phenotypic coverage in a worldwidepopulation based on the alleles found to bind each peptide. Thesealleles can be used to calculate the HLA phenotypic coverage of apeptide or a peptide combination.

TABLE 16a Table 16a - In vitro HLA Class II binding analysis of somepeptides Peptide ID DRB1_0101 DRB1_0301 DRB1_0401 DRB1_0405 DRB1_0701DRB1_0802 DRB1_0901 DRB1_1101 HDM03W HDM101A x x HDM201 x x x x x xHDM203B x x x x x x x x HDM205 x x x x x x HDM26B x x x x x HDM35A x x x002 x x x 009 x x x x x x 010 x x x x x x 011 x x x x x 012 x x x 020 xx x x x 022 x x x x x x 025 x x x x x x 031 x x x x x 041 044 x x x x xx 049 x x x x x x 050 x x x 053 x N x x 058 x x x x x x 075 x x x 089 x090 x N x x 091 x N x x x 099 x x x x 102 x N x x 109 x x x x 110 x x xx x 117 x x x x x x x x 122 x x x x x x x 123 x N x x x x x 124 N x x x125 x N x x 126 x N x x x 130 x N x x x x 131 x N x x x HLA- DQA10501-Peptide ID DRB1_1201 DRB1_1302 DRB1_1501 DRB3_0101 DRB3_0202 DRB4_0101DRB5_0101 QB10201 HDM03W HDM101A x x x HDM201 x x x x HDM203B x x x x xHDM205 x x x HDM26B x x x x x HDM35A 002 x x x 009 x x x x x 010 x x x xx x 011 x x x x x 012 x x 020 x x 022 x 025 x x x x 031 x x x x x x 041x x x x 044 x x x x 049 x x x x x x x 050 x 053 x x 058 x x x x x 075 xx x x x 089 x 090 x x x 091 x x x x 099 x x 102 x x 109 x x x 110 x x xx 117 x x x x 122 x x x 123 x x x x x x x 124 x 125 x 126 x x x 130 x xx x x 131 x x x HLA- HLA- HLA- HLA- HLA- HLA- HLA- HLA- DQA10501-DQA10301- DQA10401- DQA10101- DQA10102- DPA10201- DPA10103- DPA10103-Peptide ID DQB10301 DQB10302 DQB10402 DQB10501 DQB10602 DPB10101DPB10201 DPB10301 HDM03W HDM101A HDM201 HDM203B x x x HDM205 HDM26B x xHDM35A 002 x 009 x x 010 x x x x x x 011 x x x x 012 x 020 x x x N 022 x025 x x 031 x x 041 x N 044 x x x x x N x 049 x x N x 050 N x 053 x x N058 x x x N x 075 x x N 089 N 090 x x N 091 x N x 099 x x N 102 x x N109 N 110 x x N 117 x x 122 x 123 x x N x 124 N x x 125 x x N 126 x N x130 x x x x N x x 131 x N x x HLA- HLA- HLA- HLA- DPA10103- DPA10202-DPA10201- DPA10103- Peptide ID DPB10401 DPB10501 DPB11401 DPB10402HDM03W HDM101A x HDM201 HDM203B HDM205 HDM26B x HDM35A 002 009 x 010 x x011 x 012 x 020 022 025 031 x x 041 044 x 049 x 050 053 058 075 089 090091 099 x 102 109 110 x x 117 x 122 123 x 124 125 x 126 130 x 131 N:indicates that data was not available.

TABLE 16b Table 16b - HLA Class II phenotypic coverage of some peptidesbCutoff 1000 nM Cutoff: 300 nM Peptide Number of Population Number ofPopulation ID alleles Coverage alleles Coverage 010 20 99.5% 16 96.8%130 16 97.7% 11 91.3% 011 15 97.6% 9 74.1% 044 17 97.5% 12 87.5% 123 1697.3% 12 94.3% 049 16 97.0% 9 77.2% 058 15 94.3% 12 86.7% 009 13 92.0%10 76.7% 031 14 91.9% 7 69.9% 117 14 91.7% 10 77.5% HDM26B 12 91.7% 984.1% 110 12 91.5% 8 77.7% HDM203B 15 89.9% 11 79.5% 025 12 86.1% 637.3% 091 10 84.0% 5 71.0% 090 8 81.7% 6 76.5% 053 6 81.3% 5 67.9% 07510 81.0% 5 33.6% 102 8 80.9% 7 76.5% 020 10 80.8% 4 37.5% 131 9 79.6% 666.8% HDM201 10 79.5% 7 48.9% 002 7 77.7% 7 77.7% HDM101A 6 75.4% 325.5% HDM205 9 74.9% 3 51.4% 099 8 74.5% 5 56.5% 125 6 73.9% 4 64.0% 1097 73.7% 6 54.9% 126 8 73.4% 4 44.8% 012 6 71.5% 4 55.1% 122 10 71.2% 645.6% 041 5 68.1% 2 18.1% 124 5 60.2% 3 39.2% 022 8 54.6% 6 43.5% 050 448.1% 2 35.9% 089 2 44.7% 2 44.7% HDM35A 3 21.5% 0 0.0% HDM03W 0 0.0% 00.0%

Example 10 Prediction and Calculation of HLA Class II PhenotypicCoverage of Peptide Combinations

This example describes how HLA Class II allele coverage can bedetermined for individual peptides and peptide combination disclosedherein,

In order to elicit a T-cell response a given peptide must be able tobind to at least one HLA class II molecule in a given individual. Eachindividual express several HLA molecules, and globally, thousands ofdifferent alleles exist. Each HLA molecule can bind a limited number ofdifferent peptides and not all HLAs bind the same peptides. In order toestimate the potential coverage of a peptide in a given population, thefrequency of the different HLA class II molecules present in thepopulation, and the binding affinity of peptide towards each of thesemolecules must be available. The peptide binding to a specific HLAmolecule can be measured, for example as described in Example 9, orpredicted using in silico algorithms as e.g. NetMHCII and NetMHCIIpan(as disclosed in Example 2 or as described in Nielsen et al 2010 orNielsen et al 2009).

The exact affinity necessary for an immune response is not known, but isgenerally assumed to be in the range of 300 nM-1000 nM. The calculatedphenotypic coverage of alleles determined to bind to each peptide ispresented using either 300 nM or 1000 nM are presented in Table 16a. Forpredicted affinities is used a binding threshold of 300 nM together witha percentile rank score reported by the prediction algorithm, of atleast 30.

This example also describes how peptide combinations can be comparedwith respect to the average fraction of donors (% of patients) havingHLA Class II alleles potentially able to bind a given number of peptides(0, 1, 2, 3, 4, or 5 peptides) in a peptide combination disclosed herein(herein named valency of a peptide combination).

The HLA coverage and valency may be estimated using HLA Class II allelesrepresented in a worldwide population or in a subset thereof, forexample the subset of alleles shown in Table 16a.

To estimate the valency, a system was created that generates virtualpatients (VP). Each VP was generated using the 83 allele frequenciesfrom Table 17 as probabilities at each locus to have this particularallele. As not all alleles in the world are considered, some of thegenerated VPs will lack one or more HLAs. To estimate the averagefraction of patients reacting against a certain number of peptides, 1000VPs were generated. Using the prediction method and HLA binding affinitythresholds (300 nM and 30% fractile) earlier described herein, thenumber of peptides that an average VP would react against was predicted.In addition, the overall fraction of how many VPs would react against 0,1, 2, 3, 4 and 5 peptides, respectively, were calculated based onpredicted HLA binding compared to the measured HLA binding affinities.

FIGS. 10a, 11a, 12a show the estimated valency of peptide combinations5, 17f and 8 based on the peptides predicted HLA allele coverage to theHLA alleles shown in Table 16a, whereas FIGS. 10b, 11b and 12b show theestimated valency of the same peptide combinations based on the peptidesmeasured HLA allele coverage to the same alleles.

The data indicates high correlation between the valency data based onpredicted HLA allele coverage and measured HLA allele coverage.

FIGS. 13 to 19 show the estimated valency of peptide combinations 9 17d,17f, 17p, 17s, 17x and 23 that patients in a virtual patient populationmay respond to, wherein the estimation is based on predicted binding tothe 83 HLA alleles shown in Table 17. The estimation may include thefollowing: for each peptide or peptide combination the alleles found tobe binding the given peptide, or at least one peptide in the peptidecombination, is considered for the coverage calculation. Assuming thatalleles at different loci are independently distributed, which is notentirely true, but is a reasonably approximation, the phenotypiccoverage of the binding alleles can now be calculated using standardmethods known in the art. For example, For each HLA locus (DRB1, DRB3,DRB4, DRB5) or locus combination (DQA1-DQB1, DPA1-DPB1), the HLA allelefrequencies of all the alleles from the given locus found to bind thegiven peptide is summed (f_(sum,locus)). The total phenotypic coveragefor each locus, n (C_(n)) is calculated as(2×f_(sum,locus))−(f_(sum,locus))².

The total phenotypic coverage of all binding alleles from n loci can becalculated as

$K_{n} = {1 - {\sum\limits_{i = 1}^{n}{\left( {1 - K_{({i - 1})}} \right) \times C_{i}}}}$

where K₀=0

The FIGS. 10a to 19 show the fraction of the virtual patients (Y-axis=%patients) that have HLA Class II alleles potentially able to bind (i.e.able to respond to) 0, 1, 2, 3, 4 and 5 peptides, respectively, in thecombination (Data indicated with bars). Valency data are shown both withrespect to peptides only derived from the HDM group 1 allergens Der p 1or Der f 1 (indicated at the x-axis as Grp 1); peptides only derivedfrom the HDM group 2 allergens Der p 2 or Der f 2 (indicated at thex-axis as Grp 2); peptides derived only from Der p (i.e. allergens Der p1 or Der p 2 (indicated at the x-axis as Der p) and peptides derivedonly from Der f (i.e. allergens Der f 1 or Der f 2 (indicated at thex-axis as Der f). Finally, the valency is also shown for the allpeptides in the combination (indicated at the X-axis as “all”). TheFigures also show the predicted fraction of patients (% patients) thatwill have HLA alleles potentially able to bind a given number ofpeptides or more in the peptide combination (data points shown as X)

For example, the measured valency data of the 5-peptide combination 17f(FIG. 11b ) shows that 20% of the patients potentially are able torespond to 5 peptides, 40% of the population potentially are able torespond to 4 peptides (data indicated with bars), that 60% of thepopulation potentially are able to bind to at least 4 peptides (datapoint from curve) and that about 95% of the patients potentially areable to bind at least 2 of the 5 peptides in the combination.

The measured valency data of the 7-peptide combination 8 (FIG. 12b )shows that about 10% of the patients potentially are able to respond to5 peptides, 25% of the population potentially are able to respond to 4peptides (data indicated with bars), that 35% of the populationpotentially are able to bind to at least 4 peptides (data point fromcurve) and that about 82% of the patients potentially are able to bindat least 2 of the 6 peptides in the combination that derives from Der p1, Der p1, Der f1 or Der f2. Peptide combination 8 contains a peptidederived from Der p 7 (HDM35A), which has poor HLA allele coverage (Table16a).

TABLE 17 Table 17 - 83 HLA Class II alleles and their frequencies foruse in HLA coverage predictions HLA Alleles Frequency DRB1_0101 0.0428DRB1_0102 0.0233 DRB1_0103 0.0048 DRB1_0301 0.0773 DRB1_0302 0.0175DRB1_0307 0.0003 DRB1_0401 0.0338 DRB1_0402 0.0078 DRB1_0403 0.0158DRB1_0404 0.0275 DRB1_0405 0.0233 DRB1_0406 0.0063 DRB1_0407 0.0245DRB1_0408 0.0025 DRB1_0410 0.0025 DRB1_0411 0.0035 DRB1_0417 0.0003DRB1_0701 0.1015 DRB1_0801 0.0113 DRB1_0802 0.0273 DRB1_0803 0.0140DRB1_0804 0.0163 DRB1_0806 0.0015 DRB1_0809 0.0005 DRB1_0811 0.0005DRB1_0901 0.0395 DRB1_1001 0.0170 DRB1_1101 0.0570 DRB1_1102 0.0133DRB1_1103 0.0028 DRB1_1104 0.0185 DRB1_1106 0.0008 DRB1_1110 0.0008DRB1_1111 0.0003 DRB1_1128 0.0000 DRB1_1201 0.0233 DRB1_1202 0.0195DRB1_1301 0.0458 DRB1_1302 0.0445 DRB1_1303 0.0153 DRB1_1304 0.0040DRB1_1305 0.0020 DRB1_1307 0.0000 DRB1_1311 0.0003 DRB1_1312 0.0010DRB1_1323 0.0003 DRB1_1331 0.0003 DRB1_1401 0.0228 DRB1_1402 0.0093DRB1_1403 0.0013 DRB1_1404 0.0053 DRB1_1405 0.0045 DRB1_1406 0.0100DRB1_1407 0.0010 DRB1_1418 0.0003 DRB1_1419 0.0003 DRB1_1424 0.0003DRB1_1501 0.0740 DRB1_1502 0.0258 DRB1_1503 0.0313 DRB1_1504 0.0003DRB1_1506 0.0010 DRB1_1519 0.0000 DRB1_1601 0.0043 DRB1_1602 0.0173DRB1_1607 0.0003 DRB3_0101 0.1400 DRB3_0202 0.1890 DRB4_0101 0.2370DRB5_0101 0.0830 DPA10103-DPB10201 0.0920 DPA10103-DPB10301 0.0700DPA10103-DPB10401 0.2010 DPA10103-DPB1040 0.2360 DPA10201-DPB101010.0840 DPA10201-DPB11401 0.0380 DPA10202-DPB10501 0.1150DQA10101-DQB10501 0.0760 DQA10102-DQB10602 0.0760 DQA10301-DQ8103020.1000 DQA10401-DQB10402 0.0660 DQA10501-DQB10201 0.0580DQA10501-DQB10301 0.1950

1. A composition comprising at least three peptides, wherein thecomposition comprises peptides selected from at least three of thefollowing peptide groups: i. a parent peptide with the amino acidsequence SEQ ID NO 82 (pep-110) or a variant thereof; ii. a parentpeptide with the amino acid sequence SEQ ID NO 271 (pep-131) or avariant thereof; iii. a parent peptide with the amino acid sequence SEQID NO 268 (pep-130) or a variant thereof; wherein the variant peptideconsists of 15-25 amino acid residues and, comprises an amino acidsequence having at least 80 sequence identity over at least 15contiguous amino acids of the parent peptide; and wherein the variantpeptide binds to at least 70% of the Class HLA II alleles that theparent peptide binds to when tested under the same test conditionsand/or wherein the variant peptide and the parent peptide bothstimulates cytokine IL-5 production of allergen specific T cells underthe same in vitro test conditions.
 2. The composition according to claim1, wherein the Class HLA II alleles is selected from one or more or allof the following alleles DPA1*02:01-DPB1*01:01, DPA1*01:03-DPB1*02:01,DPA1*01:03-DPB1*03:01, DPA1*01:03-DPB1*04:01, DPA1*01:03-DPB1*04:02,DPA1*02:02-DPB1*05:01, DPA1*02:01-DPB1*14:01, DQA1*05:01-DQB1*02:01,DQA1*05:01-DQB1*03:01, DQA1*03:01-DQB1*03:02, DQA1*04:01-DQB1*04:02,DQA1*01:01-DQB1*05:01, DQA1*01:02-DQB1*06:02, DRB1*01:01, DRB1*03:01,DRB1*04:01, DRB1*04:05, DRB1*07:01, DRB1*09:01, DRB1*11:01, DRB1*12:01,DRB1*13:02, DRB1*15:01, DRB3*01:01, DRB3*02:02, DRB4*01:01 andDRB5*01:01.
 3. The composition according to claim 2, wherein thepeptides in the composition collectively bind at least 22 of the classHLA II alleles selected from the group of class HLA II alleles asdefined in claim
 2. 4. The composition according to claim 1, furthercomprising an additional peptide selected from any one of the groups:iv. a parent peptide with the amino acid sequence SEQ ID NO: 266(pep-123) or a variant thereof; v. a parent peptide with the amino acidsequence SEQ ID NO: 26 (pep-058) or a variant thereof; or vi. a parentpeptide with the amino acid sequence SEQ ID NO: 62 (pep-091) or avariant thereof; and wherein a variant peptide is as defined in claim 1.5. The composition according to claim 1, wherein the compositioncomprises a maximum of three, four, five, six or seven peptides eachfrom different groups.
 6. The composition according to claim 1, whereinthe composition comprises a maximum of five peptides from each of fivedifferent groups.
 7. The composition according to claim 1, wherein thecomposition comprises a) a parent peptide with the amino acid sequenceSEQ ID NO: 82 (pep-110) or a variant thereof; b) a parent peptide withthe amino acid sequence SEQ ID NO: 271 (pep-131) or a variant thereof;c) a parent peptide with the amino acid sequence SEQ ID NO: 268(pep-130) or a variant thereof; d) a parent peptide with the amino acidsequence SEQ ID NO: 266 (pep-123) or a variant thereof; and e) a parentpeptide with the amino acid sequence SEQ ID NO: 26 (pep-058) or avariant thereof; wherein the variant peptide consists of 15-25 aminoacid residues and comprises an amino acid sequence having at least 80%sequence identity over at least 15 contiguous amino acids of the parentpeptide; and wherein the variant peptide binds to at least 70% of theClass HLA II alleles that the parent peptide binds to when tested underthe same test conditions and/or wherein the variant peptide and theparent peptide both stimulates cytokine IL-5 production of allergenspecific T cells under the same in vitro test conditions.
 8. Thecomposition according to claim 7, wherein the composition comprises a) aparent peptide with the amino acid sequence SEQ ID NO: 82(pep-110); b) aparent peptide with the amino acid sequence SEQ ID NO: 271 (pep-131); c)a parent peptide with the amino acid sequence SEQ ID NO: 268 (pep-130);d) a parent peptide with the amino acid sequence SEQ ID NO; 266(pep-123); and e) a parent peptide with the amino acid sequence SEQ IDNO: 26 (pep-058).
 9. The composition according to claim 1, wherein thecomposition comprises a) a parent peptide with the amino acid sequenceSEQ ID NO: 82 (pep-110); b) a parent peptide with the amino acidsequence SEQ ID NO: 271 (pep-131); c) a parent peptide with the aminoacid sequence SEQ ID NO: 268 (pep-130); d) a parent peptide with theamino acid sequence SEQ ID NO: 46 (pep-075); and e) a parent peptidewith the amino acid sequence SEQ ID NO: 26 (pep-058).
 10. Thecomposition according to claim 1, wherein the composition comprises a) aparent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110) or avariant thereof; b) a parent peptide with the amino acid sequence SEQ IDNO: 271 (pep-131) or a variant thereof; c) a parent peptide with theamino acid sequence SEQ ID NO: 268 (pep-130) or a variant thereof; d) aparent peptide with the amino acid sequence SEQ ID NO: 266 (pep-123) ora variant thereof; e) a parent peptide with the amino acid sequence SEQID NO: 62 (pep-091) or a variant thereof; wherein the variant peptideconsists of 15-25 amino acid residues and comprises an amino acidsequence having at least 80% sequence identity over at least 15contiguous amino acids of the parent peptide; and wherein the variantpeptide binds to at least 70% of the Class HLA II alleles that theparent peptide binds to when tested under the same test conditionsand/or wherein the variant peptide and the parent peptide bothstimulates cytokine IL-5 production of allergen specific T cells underthe same in vitro test conditions.
 11. The composition according toclaim 10, wherein the composition comprises a) a parent peptide with theamino acid sequence SEQ ID NO: 82 (pep-110); b) a parent peptide withthe amino acid sequence SEQ ID NO: 271 (pep-131); c) a parent peptidewith the amino acid sequence SEQ ID NO: 268 (pep-130); d) a parentpeptide with the amino acid sequence SEQ ID NO: 266 (pep-123); and e) aparent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091). 12.The composition according to claim 5, wherein the composition comprisesa) a parent peptide with the amino acid sequence SEQ ID NO: 82 (pep-110)or a variant thereof; b) a parent peptide with the amino acid sequenceSEQ ID NO: 271 (pep-131) or a variant thereof; c) a parent peptide withthe amino acid sequence SEQ ID NO: 268 (pep-130) or a variant thereof;d) a parent peptide with the amino acid sequence SEQ ID NO: 26 (pep-058)or a variant thereof; e) a parent peptide with the amino acid sequenceSEQ ID NO: 62 (pep-091) or a variant thereof; wherein the variantpeptide consists of 15-25 amino acid residues and comprises an aminoacid sequence having at least 80% sequence identity over at least 15contiguous amino acids of the parent peptide; and wherein the variantpeptide binds to at least 70% of the Class HLA II alleles that theparent peptide binds to when tested under the same test conditionsand/or wherein the variant peptide and the parent peptide bothstimulates cytokine IL-5 production of allergen specific T cells underthe same in vitro test conditions.
 13. The composition according toclaim 12, wherein the composition comprises a) a parent peptide with theamino acid sequence SEQ ID NO: 82 (pep-110); b) a parent peptide withthe amino acid sequence SEQ ID NO: 271 (pep-131); c) a parent peptidewith the amino acid sequence SEQ ID NO: 268 (pep-130); d) a parentpeptide with the amino acid sequence SEQ ID NO: 26 (pep-058); and e) aparent peptide with the amino acid sequence SEQ ID NO: 62 (pep-091).14-25. (canceled)
 26. The composition according to claim 1, wherein theparent peptide or the variant thereof is amidated at the C-terminal end,or wherein the parent peptide or the variant thereof is a salt.
 27. Thecomposition according to claim 1, wherein the parent peptide or thevariant thereof is amidated at the C-terminal end.
 28. The compositionaccording to claim 1, wherein the parent peptide or the variant thereofis a salt.
 29. The composition according to claim 1, wherein thecomposition is a pharmaceutical composition.
 30. The pharmaceuticalcomposition according to claim 29, further comprising a pharmaceuticallyacceptable carrier, excipient and/or adjuvant, optionally sterile.
 31. Amethod for relieving or reducing an immune response triggered by anallergen of a dust mite in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecomposition according to claim
 1. 32. A method for relieving one or moresymptoms of an immune response triggered by an allergen of a dust mitein a subject in need thereof, comprising administering to the subject atherapeutically effective amount of the composition according toclaim
 1. 33. The method according to claim 31, wherein the methodcomprises decreasing a T cell response in the subject to an allergen ofa dust mite.
 34. (canceled)
 35. (canceled)